Inhibitors of neuraminidases

ABSTRACT

Disclosed are compounds of the formula:                    
     which are useful for inhibiting neuraminidases from disease-causing microorganisms, especially, influenza neuraminidase. Also disclosed are compositions and methods for preventing and treating diseases caused by microorganisms having a neuraminidase, processes for preparing the compounds and synthetic intermediates used in these processes.

This application is a divisional of U.S. patent application Ser. No.09/421,787, filed Oct. 19, 1999, now issued as U.S. Pat. No. 6,455,571,which is a continuation-in-part of U.S. patent application Ser. No.09/282,139, Filed Mar. 31, 1999 now abandoned, which claims priority toU.S. Provisional Application No. 60/082,828, filed Apr. 23, 1998, eachof which are incorporated herein by reference.

TECHNICAL FIELD

The present invention relates to novel compounds, compositions andmethods for inhibiting neuraminidase, especially influenzaneuraminidase. The invention also contemplates a composition and methodsfor preventing and treating an influenza infection and processes formaking such compounds and synthetic intermediates employed in theseprocesses.

BACKGROUND OF THE INVENTION

Many disease causing microorganisms possess a neuraminidase (also knownas sialidase) which is involved in the replication process of themicroorganism. In particular, viruses of the orthomyxovirus andparamyxovirus groups possess a neuraminidase. Diseases associated withparamyxoviruses include RSV (respiratory syncytial virus-relateddiseases), pneumonia and bronchiolitis (associated with paramyxovirustype 3) and laryngotracheobronchitis (associated with paramyxovirus type1). Some of the more important disease-causing microorganisms in manand/or animals which possess a neuraminidase include Vibrio cholerae,Clostridium perfringens, Streptococcus pneumoniae, Arthrobactersialophilus, influenza virus, parainfluenza virus, mumps virus,Newcastle disease virus, fowl plague virus, equine influenza virus andSendai virus.

Mortality due to influenza is a serious problem throughout the world.The disease is devastating to man, lower mammals and some birds.Although vaccines containing attenuated influenza virus are available,those vaccines only provide immunological protection toward a fewinfluenza strains and are less effective in otherwise immunologicallycompromised populations such as the elderly, young children, and inthose who suffer from chronic respiratory illness. The productivity lossfrom absence due to sickness from influenza virus infection has beenestimated to be more than $1 billion per year.

There are two major strains of influenza virus (designated A and B).Currently, there are only a few pharmaceutical products approved fortreating influenza. These include amantadine and rimantadine, which areactive only against the A strain of influenza viruses, and ribavirin,which suffers from dose-limiting toxicity. Mutant virus which isresistant to amantadine and rimantadine emerges quickly during treatmentwith these agents.

Very recently the first influenza neuraminidase inhibitor, zanamivir,was approved. However, it can only be administered by inhalation.Therefore, there is a continuing need for improved agents for treatmentand/or prevention of influenza infection.

Neuraminidase is one of two major viral proteins which protrude from theenvelope of influenza virus. During the release of progeny virus frominfected cells, neuraminidase cleaves terminal sialic acid residues fromglycoproteins, glycolipids and oligosaccharides on the cell surface.Inhibition of neuraminidase enzymatic activity leads to aggregation ofprogeny virus at the surface. Such virus is incapable of infecting newcells, and viral replication is therefore retarded or blocked. X-raycrystallographic studies and sequence alignments have shown that theresidues which directly contact the sialic acid portion of the substrateare strictly conserved in the neuraminidase from all A and B influenzastrains. Thus, a compound which binds to the sialic acid binding regionof the neuraminidase active site will block the replication of both theA and B strains of influenza virus. Compounds which are influenzaneuraminidase inhibitors will be useful for the prevention of influenzainfection and will be useful for the treatment of influenza infection.

The following references disclose neuraminic acid derivatives with thedisclosed utility listed after each reference:

L. Von Itzstein, et al., European Patent Application No. EP539204,published Apr. 28, 1993 (antiviral agent);

T. Honda; et al., European Patent Application No. EP823428, publishedFeb. 11, 1998 (sialidase inhibitor; influenza treatment);

T. Honda, et al., International Patent Application No. WO98/06712,published Feb. 19, 1998 (sialidase inhibitor; influenza remedy);

L. Von Itzstein, et al., International Patent Application No.WO95/20583, published Aug. 3, 1995 (viral neuraminidase inhibitor;influenza treatment);

P. Smith, International Patent Application No. WO95/18800, publishedJul. 13, 1995 (viral neuraminidase inhibitor);

P. Colman, et al., International Patent Application No. WO92/06691,published Apr. 30, 1992 (viral neuraminidase inhibitor);

L. Von Itzstein, et al., U.S. Pat. No. 5,648,379, issued Jul. 15, 1997(influenza treatment);

P. Reece, et al., International Patent Application No. WO97/32214,published Sep. 4, 1997 (bind to influenza virus neuraminidase activesite), and

P. Reece, et al., International Patent Application No. WO98/21243,published May 23, 1998 (anti-influenza agent).

The following references disclose sialic acid derivatives with thedisclosed utility listed after each reference:

Y. Ohira, et al., International Patent Application No. WO98/11083,published Mar. 19, 1998 (antiviral agent);

Y. Ohira, European Patent Application No. EP882721, published Dec. 9,1998 (antiviral agent); and

B. Glanzer, et al., Helvetica Chimica Acta 74 343-369 (1991) (Vibriocholerae neuraminidase inhibitor).

The following references disclose benzene derivatives, cyclohexanederivatives or cyclohexene derivatives with the disclosed utility listedafter each reference:

Y. Babu, et al., U.S. Pat. No. 5,602,277, issued Feb. 11, 1997(neuraminidase inhibitors);

M. Luo, et al., U.S. Pat. No. 5,453,533, issued Sep. 26, 1995 (influenzaneuraminidase inhibitor; influenza treatment);

Y. Babu, et al., International Patent Application No. WO96/30329,published Oct. 3, 1996 (neuraminidase inhibitor; viral infectiontreatment);

N. Bischofberger, et al., U.S. Pat. No. 5,763,483, issued Jun. 9, 1998(neuraminidase inhibitor);

C. Kim, et al., International Patent Application No. WO99/31047,published Jun. 24, 1999 (neuraminidase inhibitor; influenza treatment);

V. Atigadda, et al., J. Med. Chem. 42 2332-2343 (1999) (influenzaneuraminidase inhibitor); and

K. Kent, et al., International Patent Application No. 98/07685,published Feb. 26, 1998 (intermediates for the preparation ofneuraminidase inhibitors).

C. Kim, et al., International Patent Application No. WO98/17647,published Apr. 30, 1998 discloses piperidine derivatives that are usefulas neuraminidase inhibitors.

N. Bischofberger, et al., International Patent Application No.WO96/26933, published Sep. 6, 1996 and N. Bischofberger, et al.,International Patent Application No. WO99/14185, published Mar. 25, 1999disclose various substituted 6-membered ring compounds that are usefulas neuraminidase inhibitors.

The following references disclose dihydropyran derivatives that areuseful as viral neuraminidase inhibitors:

D. Andrews, et al., International Patent Application No. WO97/06157,published Feb. 20, 1997 and U.S. Pat. No. 5,919,819, issued Jul. 6,1999; and

P. Cherry, et al., International Patent Application No. WO96/36628,published Nov. 21, 1996.

C. Kim, et al., U.S. Pat. No. 5,512,596, issued Apr. 30, 1996 discloses6-membered aromatic ring derivatives that are useful as neuraminidaseinhibitors.

G. Diana, et al., International Patent Application No. WO98/03487,published Jan. 29, 1998 discloses substituted pyridazines that areuseful for treatment of influenza.

B. Horenstein, et al., International Patent Application No. WO99/06369,published Feb. 11, 1999 discloses piperazine derivatives that are usefulas neuraminidase inhibitors.

The following references disclose substituted cyclopentanes that areuseful as neuraminidase inhibitors and treatments for influenza:

Y. Babu, et al., International Patent Application No. WO97/47194,published Dec. 18, 1997; and

Y. Babu, et al., International Patent Application No. WO99/33781,published Jul. 8, 1999.

L. Czollner, et al., Helvetica Chimica Acta 73 1338-1358 (1990)discloses pyrrolidine analogs of neuraminic acid that are useful asVibrio cholerae sialidase inhibitors.

W. Brouillette, et al., International Patent Application No. WO99/14191,published Mar. 25, 1999, discloses substituted pyrrolidin-2-onecompounds that are useful as neuraminidase inhibitors and treatments forinfluenza.

The following references disclose siastatin B analogs that are useful asneuraminidase inhibitors:

Y. Nishimura, et al., Natural Product Letters 1 3944 (1992); and

Y. Nishimura, et al., Natural Product Letters 1 33-38 (1992).

C. Penn, UK Patent Application No. GB2292081, published Feb. 14, 1996discloses the use of a neuraminidase inhibitor in combination with aninfluenza vaccine.

An object of the invention is to provide compounds that inhibitneuraminidase of disease-causing microorganisms; especially, viralneuraminidase; and, most especially influenza neuraminidase.

An object of the invention is also to provide compounds that inhibitneuraminidase from both A and B strains of influenza.

Another object of the invention is to provide prophylaxis of influenzainfection in humans and other mammals.

Another object of the invention is to provide treatment of influenzainfection in humans and other mammals.

Another object of the invention is to provide compounds that exhibitactivity against influenza A virus and influenza B virus by virtue ofinhibiting influenza neuraminidase when such compounds are administeredorally.

Another object of the invention is to provide a compound that can beeffectively transported from the plasma into the lung bronchoaveolarfluid of humans and other mammals in order to block the replication ofinfluenza virus in that tissue.

DISCLOSURE OF THE INVENTION

The present invention discloses compounds having Formula I:

or a pharmaceutically acceptable salt, ester or prodrug thereof,

wherein R¹ is selected from the group consisting of

(a) —CO₂H, (b) —CH₂CO₂H, (c) —SO₃H, (d) —CH₂SO₃H, (e) —SO₂H, (f)—CH₂SO₂H, (g) —PO₃H₂, (h) —CH₂PO₃H₂, (i) —PO₂H, (j) —CH₂PO₂H, (k)tetrazolyl, (l) —CH₂-tetrazolyl, (m) —C(═O)—NH—S(O)₂—R¹¹, (n)—CH₂C(═O)—NH—S(O)₂—R¹¹, (o) —SO₂N(T—R¹¹)R¹² and (p) —CH₂SO₂N(T—R¹¹)R¹²

wherein T is selected from the group consisting of

(i) a bond, (ii) —C(═O)—, (iii) —C(═O)O—, (iv) —C(═O)S—, (v)—C(═O)NR³⁶—, (vi) —C(═S)O—, (vii) —C(═S)S—, and (viii) —C(═S)NR³⁶—,

R¹¹ is selected from the group consisting of

(i) C₁-C₁₂ alkyl, (ii) C₂-C₁₂ alkenyl, (iii) cycloalkyl, (iv)(cycloalkyl)alkyl, (v) (cycloalkyl)alkenyl, (vi) cycloalkenyl, (vii)(cycloalkenyl)alkyl, (viii) (cycloalkenyl)alkenyl, (ix) aryl, (x)(aryl)alkyl, (xi) (aryl)alkenyl, (xii) heterocyclic, (xiii)(heterocyclic)alkyl and (xiii) (xiv) (heterocyclic)alkenyl; and

R¹² and R³⁶ are independently selected from the group consisting of

(i) hydrogen, (ii) C₁-C₁₂ alkyl, (iii) C₂-C₁₂ alkenyl, (iv) cycloalkyl,(v) (cycloalkyl)alkyl, (vi) (cycloalkyl)alkenyl, (vii) cycloalkenyl,(viii) (cycloalkenyl)alkyl, (ix) (cycloalkenyl)alkenyl, (x) aryl, (xi)(aryl)alkyl, (xii) (aryl)alkenyl, (xiii) heterocyclic, (xiv)(heterocyclic)alkyl and (xv) (heterocyclic)alkenyl;

X is selected from the group consisting of

(a) —C(═O)—N(R*)—, (b) —N(R*)—C(═O)—, (c) —C(═S)—N(R*)—, (d)—N(R*)—C(═S)—, (e) —N(R*)—SO₂—, and (f) —SO₂—N(R*)— wherein R* ishydrogen, C₁-C₃ loweralkyl or cyclopropyl;

R² is selected from the group consisting of

(a) hydrogen, (b) C₁-C₆ alkyl, (c) C₂-C₆ alkenyl, (d) C₃-C₆ cycloalkyl,(e) C₅-C₆ cycloalkenyl, (f) halo C₁-C₆ alkyl and (g) halo C₂-C₆ alkenyl;

or R²—X— is

wherein Y¹ is —CH₂, —O—, —S— or —NH— and Y² is —C(═O)— or—C(R^(aa))(R^(bb))— wherein R^(aa) and R^(bb) are independently selectedfrom the group consisting of hydrogen,

C₁-C₃ loweralkyl, hydroxymethyl, 1-hydroxyethyl, 2-hydroxyethyl,aminomethyl, 1-aminoethyl, 2-aminoethyl, thiolmethyl, 1-thiolethyl,2-thiolethyl, methoxymethyl, N-methylaminomethyl and methylthiomethyl;

R³ and R⁴ are independently selected from the group consisting of

(a) hydrogen, (b) cycloalkyl, (c) cycloalkenyl, (d) heterocyclic, (e)aryl and (f) —Z—R¹⁴

wherein Z is

(i) —C(R^(37a))(R^(37b))—, (ii) —C(R⁴⁷)═C(R⁴⁸)—, (iii) —C≡C—, (iv)—C(═O)—,

(v) —C(═S)—, (vi) —C(═NR¹⁵)—, (vii) —C(R^(37a))(OR^(37c))—, (viii)—C(R^(37a))(SR^(37c))—,

(ix) —C(R^(37a))(N(R^(37b))(R^(37c)))—, (x) —C(R^(37a))(R^(37b))—O—,

(xi) —C(R^(37a))(R^(37b))—N(R^(37c))—, (xii)—C(R^(37a))(R^(37b))—N(O)(R^(37c))—,

(xiii) —C(R^(37a))(R^(37b))—N(OH)—, (xiv) —C(R^(37a))(R^(37b))—S—,

(xv) —C(R^(37a))(R^(37b))—S(O)—, (xvi) —C(R^(37a))(R^(37b))—S(O)₂—,

(xvii) —C(R^(37a))(R^(37b))—C(═O)—, (xviii) —C(R^(37a))(R^(37b))—C(═S)—,

(xix) —C(R^(37a))(R^(37b))—C(═NR¹⁵)—, (xx) C(R^(37a))(OR^(37c))—C(═O)—,

(xxi) —C(R^(37a))(SR^(37c))—C(═O)—, (xxii) C(R^(37a))(OR^(37c))—C(═S)—,

(xxiii) —C(R^(37a))(SR^(37c))—C(═S)—, (xxiv)—C(═O)—C(R^(37a))(OR^(37c))—,

(xxv) —C(═O)—C(R^(37a))(SR^(37c))—, (xxvi) —C(═S)—C(R^(37a))(OR^(37c))—,

(xxvii) —C(═S)—C(R^(37a))(SR^(37c))—, (xxviii)—C(R^(37a))(OR^(37c))—C(R^(37a))(OR^(37c))—,

(xxix) —C(R^(37a))(SR^(37c))—C(R^(37a))(OR^(37c))—,

(xxx) —C(R^(37a))(OR^(37c))—C(R^(37a))(SR^(37c))—,

(xxxi) —C(R^(37a))(SR^(37c))—C(R^(37a))(SR^(37c))—, (xxxii)—C(═O)—C(═O)—,

(xxxiii) —C(═S)—C(═S)—, (xxxiv) —C(═O)—O—, (xxxv) —C(═O)—S—,

(xxxvi) —C(═S)—O—, (xxxvii) —C(═S)—S—, (xxxviii) —C(═O)—N(R^(37a))—,

(xxxix) —C(═S)—N(R^(37a))—, (xl) —C(R^(37a))(R^(37b))—C(═O)—N(R^(37a))—,

(xli) —C(R^(37a))(R^(37b))—C(═S)—N(R^(37a))—, (xlii)—C(R^(37a))(R^(37b))—C(═O)—O—,

(xliii) —C(R^(37a))(R^(37b))—C(═O)—S—, (xliv)—C(R^(37a))(R^(37b))—C(═S)—O—,

(xlv) —C(R^(37a))(R^(37b))—C(═S)—S—, (xlvi)—C(R^(37a))(R^(37b))—N(R^(37b))—C(═O)—,

(xlvii) —C(R^(37a))(R^(37b))—N(R^(37b))—C(═S)—, (xlviii)—C(R^(37a))(R^(37b))—O—C(═O)—,

(xlix) —C(R^(37a))(R^(37b))—S—C(═O)—, (l) —C(R^(37a))(R^(37b))—O—C(═S)—,

(li) —C(R^(37a))(R^(37b))—S—C(═S)—, (lii)—C(R^(37a))(R^(37b))—N(R^(37b))—C(═O)—N(R^(37a))—,

(liii) —C(R^(37a))(R^(37b))—N(R^(37b))—C(═S)—N(R^(37a))—,

(liv) —C(R^(37a))(R^(37b))—N(R^(37b))—C(═O)—O—,

(lv) —C(R^(37a))(R^(37b))—N(R^(37b))—C(═O)—S—,

(lvi)—C(R^(37a))(R^(37b))—N(R^(37b))—C(═S)—O—,

(lvii) —C(R^(37a))(R^(37b))—N(R^(37b))—C(═S)—S—,

(lviii) —C(R^(37a))(R^(37b))—O—C(═O)—N(R^(37a))—,

(lix) —C(R^(37a))(R^(37b))—S—C(═O)—N(R^(37a))—,

(lx) —C(R^(37a))(R^(37b))—O—C(═S)—N(R^(37a))—,

(lxi) —C(R^(37a))(R^(37b))—S—C(═S)—N(R^(37a))—, (lxii)—C(R^(37a))(R^(37b))—O—C(═O)—O—,

(lxiii) —C(R^(37a))(R^(37b))—S—C(═O)—O—, (lxiv)—C(R^(37a))(R^(37b))—O—C(═O)—S—,

(lxv) —C(R^(37a))(R^(37b))—S—C(═O)—S—, (lxvi)—C(R^(37a))(R^(37b))—O—C(═S)—O—,

(lxvii) —C(R^(37a))(R^(37b))—S—C(═S)—O—, (lxviii)—C(R^(37a))(R^(37b))—O—C(═S)—S—,

(lxix) —C(R^(37a))(R^(37b))—S—C(═S)—S— or (lxx)—C(R^(37a))(R^(37b))—C(R^(37a))(OR^(37c))—;

R¹⁴ is

(i) hydrogen, (ii) C₁-C₁₂ alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,

(v) thiol-substituted alkyl, (vi) R^(37c)—O-substituted alkyl,

(vii) R^(37c)—S-substituted alkyl, (viii) aminoalkyl,

(ix) (R^(37c))NH-substituted alkyl, (x) (R^(37a))(R^(37c))N-substitutedalkyl,

(xi) R^(37a)O—(O═)C-substituted alkyl, (xii) R^(37a)S—(O═)C-substitutedalkyl, (xiii) R^(37a)O—(S═)C-substituted alkyl,

(xiv) R^(37a)S—(S═)C-substituted alkyl,

(xv) (R^(37a)O)₂—P(═O)-substituted alkyl, (xvi) cyanoalkyl,

(xvi) C₂-C₁₂ alkenyl, (xviii) haloalkenyl, (xix) C₂-C₁₂ alkynyl,

(xx) cycloalkyl, (xxi) (cycloalkyl)alkyl, (xxii) (cycloalkyl)alkenyl,

(xxiii) (cycloalkyl)alkynyl, (xxiv) cycloalkenyl,

(xxv) (cycloalkenyl)alkyl,

(xxvi) (cycloalkenyl)alkenyl, (xxvii) (cycloalkenyl)alkynyl, (xxviii)aryl,

(xxix) (aryl)alkyl, (xxx) (aryl)alkenyl, (xxxi) (aryl)alkynyl,

(xxxii) heterocyclic, (xxxiii) (heterocyclic)alkyl,

(xxxiv) (heterocyclic)alkenyl or (xxxv) (heterocyclic)alkynyl,

with the proviso that R¹⁴ is other than hydrogen when Z is

—C(R^(37a))(R^(37b))—N(R^(37b))—C(═O)—O—,—C(R^(37a))(R^(37b))—N(R^(37b))—C(═S)—O—,—C(R^(37a))(R^(37b))—N(R^(37b))—C(═S)—S—,—C(R^(37a))(R^(37b))—N(R^(37b))—C(═S)—S—,—C(R^(37a))(R^(37b))—O—C(═O)—O—, —C(R^(37a))(R^(37b))—O—C(═S)—O—,—C(R^(37a))(R^(37b))—S—C(═O)—O—, —C(R^(37a))(R^(37b))—S—C(═S)—O—,—C(R^(37a))(R^(37b))—O—C(═O)—S—, —C(R^(37a))(R^(37b))—O—C(═S)—S—,—C(R^(37a))(R^(37b))—S—C(═O)—S— or —C(R^(37a))(R^(37b))—S—C(═S)—S—;

R^(37a), R^(37b), R⁴⁷, and R⁴⁸ at each occurrence are independentlyselected from the group consisting of

(i) hydrogen, (ii) C₁-C₁₂ alkyl, (iii) haloalkyl, (iv) hydroxyalkyl,

(v) alkoxyalkyl, (vi) C₂-C₁₂ alkenyl, (vii) haloalkenyl,

(viii) C₂-C₁₂ alkynyl, (ix) cycloalkyl,

(x) (cycloalkyl)alkyl, (xi) (cycloalkyl)alkenyl, (xii)(cycloalkyl)alkynyl,

(xiii) cycloalkenyl, (xiv) (cycloalkenyl)alkyl, (xv)(cycloalkenyl)alkenyl,

(xvi) (cycloalkenyl)alkynyl, (xvii) aryl, (xviii) (aryl)alkyl,

(xix) (aryl)alkenyl, (xx) (aryl)alkynyl, (xxi) heterocyclic,

(xxii) (heterocyclic)alkyl, (xxiii) (heterocyclic)alkenyl and

(xxiv) (heterocyclic)alkynyl;

R^(37c) at each occurrence is independently selected from the groupconsisting of

(i) hydrogen, (ii) C₁-C₁₂ alkyl, (iii) haloalkyl, (iv) C₂-C₁₂ alkenyl,

(v) haloalkenyl, (vi) C₂-C₁₂ alkynyl, (vii) cycloalkyl,

(viii) (cycloalkyl)alkyl, (ix) (cycloalkyl)alkenyl, (x)(cycloalkyl)alkynyl,

(xi) cycloalkenyl, (xii) (cycloalkenyl)alkyl, (xiii)(cycloalkenyl)alkenyl,

(xiv) (cycloalkenyl)alkynyl, (xv) aryl, (xvi) (aryl)alkyl,

(xvii) (aryl)alkenyl, (xviii) (aryl)alkynyl, (xix) heterocyclic,

(xx) (heterocyclic)alkyl, (xxi) (heterocyclic)alkenyl,

(xxii) (heterocyclic)alkynyl, (xxiii) —C(═O)—R⁴, (xxiv) —C(═S)—R¹⁴,

(xxv) —S(O)₂—R¹⁴ and (xxvi) hydroxyalkyl;

or when Z is —C(R^(37a))(R^(37b))—N(R^(37c))—, then N(R^(37c)) and R¹⁴when taken together are an azido group;

or when Z is —C(R^(37a))(R^(37b))—N(O)(R^(37c))—, then N(O)(R^(37c)) andR¹⁴ when taken together are an N-oxidized 3-7 membered heterocyclic ringhaving at least one N-oxidized ring nitrogen atom;

or when Z is —C(R^(37a))(R^(37b))—, —C(R^(37a))(OR^(37c))—,—C(R^(37a))(SR^(37c)) or —C(R^(37a))(N(R^(37a))(R^(37c)))—, thenR^(37a), R¹⁴ and the carbon atom to which they are bonded when takentogether form a cyclopentyl, cyclopentenyl, cyclohexyl or cyclohexenylring or then OR^(37c) or SR^(37c) or N(R^(37c)) and R¹⁴ and the carbonatom to which they are bonded when taken together form a heterocyclicring containing an O, S or N atom, respectively, and having from 4 to 8ring atoms;

R¹⁵ is selected from the group consisting of

(i) hydrogen, (ii) hydroxy, (iii) amino, (iv) C₁-C₁₂ alkyl, (v)haloalkyl,

(vi) C₂-C₁₂ alkenyl, (vii) haloalkenyl, (viii) cycloalkyl,

(ix) (cycloalkyl)alkyl, (x) (cycloalkyl)alkenyl, (xi) cycloalkenyl,

(xii) (cycloalkenyl)alkyl, (xiii) (cycloalkenyl)alkenyl, (xiv) aryl,

(xv) (aryl)alkyl, (xvi) (aryl)alkenyl, (xvii) heterocyclic,

(xviii) (heterocyclic)alkyl and (xix) (heterocyclic)alkenyl;

or R³ and R⁴ taken together, with the atom to which they are attached,form a carbocyclic or heterocyclic ring having from 3 to 8 ring atoms;

R⁵ is selected from the group consisting of

(a) hydrogen, (b) —CH(R³⁸)₂, (c) —O—R⁴⁰, (d) C₂C₄ alkynyl, (e)cyclopropyl, (f) cyclobutyl, (g) —C(═Q¹)—R¹⁷, and (h) —N(R¹⁹)₂

wherein Q¹ is O, S, or N(R¹⁵);

R¹⁷ and R¹⁸ are independently selected, at each occurrence, from thegroup consisting of hydrogen, methyl, and ethyl;

R¹⁹, R³⁸, and R⁴⁰ are independently selected, at each occurrence, fromthe group consisting of

(i) hydrogen, (ii) C₁-C₁₂ alkyl, (iii) haloalkyl, (iv) C₂-C₁₂ alkenyl,

(v) haloalkenyl, (vi) cycloalkyl, (vii) (cycloalkyl)alkyl,

(viii) (cycloalkyl)alkenyl, (ix) cycloalkenyl, (x) (cycloalkenyl)alkyl,

(xi) (cycloalkenyl)alkenyl, (xii) aryl, (xiii) (aryl)alkyl, (xiv)(aryl)alkenyl,

(xv) heterocyclic, (xvi) (heterocyclic)alkyl and

(xvii) (heterocyclic)alkenyl;

Y is selected from the group consisting of

(a) hydrogen, (b) C₁-C₅ alkyl, (c) C₁-C₅ haloalkyl, (d) C₂-C₅ alkenyl,(e) C₂-C₅ haloalkenyl, (f) C₂-C₅ alkynyl, (g) C₃-C₅ cycloalkyl, (h)C₃-C₅ cycloalkyl-C₁-to-C₃-alkyl, (i) C₅ cycloalkenyl, (j) C₅cycloalkenyl-C₁-to-C₃-alkyl, (k) C₅ cycloalkenyl-C₂-to-C₃-alkenyl, (l)—(CHR³⁹)_(n)OR²⁰, (m) —CH(OR²)—CH₂(OR²⁰), (n) —(CHR³⁹)_(n)SR²¹, (o)—(CHR³⁹)_(n)CN, (p) —(CHR³⁹)_(n)N₃, (q) phenyl, (r) halo-substitutedphenyl, (s) —(CHR³⁹)_(n)C(═Q²)R²², (t) —(CHR³⁹)_(n)N(═Q³), (u)—N(O)═CHCH₃, (v) —(CHR³⁹)_(n)NR²³R²⁴, (w) halo and (x) a heterocyclicring having from 3 to 6 ring atoms;

wherein n is 0, 1, or 2; Q² is O, S, NR²⁵, or CHR²⁶; and Q³ is NR⁴¹, orCHR⁴²;

R²⁰ at each occurrence is independently

(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,(vi) C₁-C₃ haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl,(x) allyl, (xi) C₂-C₃ haloalkenyl, (xii) amino, (xiii) —NHCH₃, (xiv)—N(CH₃)₂, (xv) —NHCH₂CH₃, (xvi) —N(CH₃)(CH₂CH₃), (xvii) —N(CH₂CH₃)₂ or

(xviii) —N(═CH₂);

R²¹ is

hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl, (vi)C₁-C₃ haloalkyl, (vii) vinyl, (viii) propenyl, (ix) isopropenyl, (x)allyl or (xi) C₂-C₃ haloalkenyl;

R²² is

(i) hydrogen, (ii) methyl, (iii) ethyl, (iv) n-propyl, (v) isopropyl,

(vi) hydroxy, (vii) thiol, (viii) methoxy, (ix) ethoxy, (x) n-propoxy,

(xi) isopropoxy, (xii) cyclopropyloxy, (xiii) methylthio, (xiv)ethylthio,

(xv) n-propylthio, (xvi) isopropylthio, (xvii) cyclopropylthio, (xviii)vinyl,

(xix) propenyl, (xx) isopropenyl, (xxi) allyl, (xxii)—N(R^(28a))(R^(28b)),

(xxiii) —CH₂R²⁹, (xxiv) aminomethyl, (xxv) hydroxymethyl,

(xxvi) thiolmethyl, (xxvii) —NHNH₂, (xxviii) —N(CH₃)NH₂ or

(xxix) —NHNH(CH₃);

R²³ and R³⁹ are independently hydrogen or methyl;

R⁴¹ and R⁴² are independently hydrogen, methyl, or ethyl;

R²⁴ is selected from the group consisting of

(i) hydrogen, (ii) C₁-C₄ alkyl, (iii) C₂-C₄ alkenyl, (iv) C₂-C₄ alkynyl,(v) cyclopropyl, (vi) —C(═Q⁴)—R³⁰, (v) —OR³¹, and (vi) —N(R³²)₂;

wherein Q⁴ is O, S, or N(R³³);

R²⁵ is hydrogen, hydroxy, methyl, ethyl, amino, —CN, or —NO₂;

R²⁶ group is hydrogen, methyl or ethyl;

R^(28a) hydrogen, hydroxy, methyl, ethyl, amino, —NHCH₃, —N(CH₃)₂,methoxy, ethoxy, or —CN;

R^(28b) is hydrogen, methyl or ethyl;

or R^(28a), R^(28b) and the nitrogen to which they are bonded takentogether represent azetidinyl;

R²⁹ group is hydrogen, hydroxy, thiol, methyl, ethyl, amino, methoxy,ethoxy, methylthio, ethylthio, methylamino or ethylamino;

R³⁰ group is hydrogen, methyl, ethyl, —OR³⁴, —SR³⁴, —N(R³⁵)₂, —NHOH,—NHNH₂, —N(CH₃)NH₂, or —N(CH₂CH₃)NH₂;

R³¹ and R³² substituents, at each occurrence, are independentlyhydrogen, methyl or ethyl;

R³³ group is hydrogen, hydroxy, methyl, ethyl, amino, —CN, or —NO₂;

R³⁴ group is methyl or ethyl;

R³⁵ group is independently hydrogen, methyl or ethyl;

with the proviso that when Q² is CHR²⁶ then R²² is selected from thegroup consisting of hydrogen, —CH₃, —C₂H₅, —C₃H₇, —OCH₃, —SCH₃, —O—C₂H₅,and —S—C₂H₅,

and with the proviso that when R³ and R⁴ are each hydrogen, then Y isother than hydrogen;

R⁶ and R⁷ are independently selected from the group consisting of

(a) hydrogen, (b) C₁-C₁₂ alkyl, (c) C₂-C₁₂ alkenyl, (d) cycloalkyl, (e)(cycloalkyl)alkyl, (f) (cycloalkyl)alkenyl, (g) cycloalkenyl, (h)(cycloalkenyl)alkyl, (i) (cycloalkenyl)alkenyl, Q) aryl, (k)(aryl)alkyl, (l) (aryl)alkenyl, (m) heterocyclic, (n)(heterocyclic)alkyl and (o) (heterocyclic)alkenyl; and

R⁸, R⁹, and R¹⁰ are independently selected from the group consisting of

(a) hydrogen, (b) C₁-C₆ alkyl, (c) C₂-C₆ alkenyl, (d) C₃-C₆ cycloalkyl,(e) C₃-C₆ cycloalkenyl, and (f) fluorine, with the proviso that thetotal number of atoms, other than hydrogen, in each of R⁸, R⁹, and R¹⁰,is 6 atoms or less.

Preferred compounds of the invention are compounds having the relativesterochemistry depicted by Formula IIA:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X and Y are as defined aboveand wherein R³ and R⁴ are not both the same.

More preferred compounds of the invention are enantiomerically enrichedcompounds having the absolute sterochemistry depicted by Formula IIB:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X and Y are as defined aboveand wherein R³ and R⁴ are not both the same.

Other preferred compounds of the invention are compounds having therelative sterochemistry depicted by Formula IIIA:

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X and Y are as defined aboveand wherein R³ and R⁴ are not both the same.

Other more preferred compounds of the invention are enantiomericallyenriched compounds having the absolute sterochemistry depicted byFormula

or a pharmaceutically acceptable salt, ester or prodrug thereof, whereinR¹, R², R³, R⁴, R⁵, R⁶, R⁷, R⁸, R⁹, R¹⁰, X and Y are as defined aboveand wherein R³ and R⁴ are not both the same.

Other preferred compounds of the invention are compounds having FormulaI, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R¹is defined as above;

—X—R² is R²—C(═O)—NH—, R²—NH—C(═O)—, R²—NH—SO₂— or R²—SO₂—NH— wherein R²is C₁-C₃ loweralkyl, halo C₁-C₃ loweralkyl, C₂-C₃ alkenyl or halo C₂-C₃alkenyl or —X—R² is

 wherein Y¹ is —CH₂—, —O—, —S— or —NH— and Y² is —C(═O)— or—C(R^(aa))(R^(bb))— wherein R^(aa) and R^(bb) are independently selectedfrom the group consisting of hydrogen, C₁-C₃ loweralkyl, hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl,thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl,N-methylaminomethyl and methylthiomethyl;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and—Z—R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ andR⁴ is other than hydrogen;

R⁵ is hydrogen or loweralkyl;

R⁶ and R⁷ are independently hydrogen or loweralkyl;

R⁸ and R⁹ are independently hydrogen, fluoro or loweralkyl;

R¹⁰ is hydrogen, fluoro or loweralkyl; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl, —C(═Q²)R²², —N(═Q³), —N(O)═CHCH₃,—NR²³R²⁴ or a heterocyclic ring having from 3 to 6 ring atoms, whereinR²², R²³, R²⁴, Q² and Q³ are defined as above.

More preferred compounds of the invention are compounds having FormulaI, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereof wherein R¹is defined as above;

—X—R² is R²—C(═O)—NH—, R²—NH—C(═O)—, R²—NH—SO₂— or R²—SO₂—NH— wherein R²is C₁-C₃ loweralkyl, halo C₁-C₃ loweralkyl, C₂-C₃ alkenyl or halo C₂-C₃alkenyl or —X—R² is

 wherein Y¹ is —CH₂— and Y² is —C(═O)— or —C(R^(aa))(R^(bb))— whereinR^(aa) and R^(bb) are independently selected from the group consistingof hydrogen, C₁-C₃ loweralkyl, hydroxymethyl, 1-hydroxyethyl and2-hydroxyethyl;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and—Z—R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ andR⁴ is other than hydrogen;

R⁵ is hydrogen or loweralkyl;

R⁶ and R⁷ are independently hydrogen or loweralkyl;

R⁸ and R⁹ are independently hydrogen or loweralkyl;

R¹⁰ is hydrogen or loweralkyl; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl, —C(═Q²)R²², —N(═Q³), —N(O)═CHCH₃,—NR²³R²⁴ or a heterocyclic ring having 5 ring atoms and also containingone or two double bonds, wherein R²², R²³, R²⁴, Q² and Q³ are defined asabove.

Even more preferred compounds of the invention are compounds havingFormula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereofwherein R¹ is defined as above; —X—R² is R²—C(═O)—NH—, R²—NH—C(═O)—,R²—NH—SO₂— or R²—SO₂—NH— wherein R² is C₁-C₃ loweralkyl, halo C₁-C₃loweralkyl, C₂-C₃ alkenyl or halo C₁-C₃ alkenyl or —X—R² is

wherein Y¹ is CH₂— and Y² is —C(═O) or —C(R^(aa))(R^(bb))— whereinR^(aa) and R^(bb) are independently selected from the group consistingof hydrogen, C₁-C₃ loweralkyl, hydroxymethyl, 1-hydroxyethyl and2-hydroxyethyl;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and—Z—R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ andR⁴ is other than hydrogen;

R⁵ is hydrogen or loweralkyl;

R⁶ and R⁷ are independently hydrogen or loweralkyl;

R⁸ and R⁹ are independently hydrogen or loweralkyl;

R¹⁰ is hydrogen or loweralkyl; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl, NH₂, —NHC(═NH)NH₂ or aheterocyclic ring having 5 ring atoms and also containing one or twodouble bonds.

More highly preferred compounds of the invention are compounds havingFormula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereofwherein R¹ is —CO₂H;

—X—R² is R²—C(═O)—NH—, R²—NH—C(═O)—, R²—NH—SO₂— or R²—SO₂—NH— wherein R²is C₁-C₃ loweralkyl or halo-C₁-C₃ loweralkyl;

R³ and R⁴ are independently selected from hydrogen, heterocyclic and—Z—R¹⁴ wherein Z and R¹⁴ are defined as above and wherein one of R³ andR⁴ is other than hydrogen;

R⁵ is hydrogen or loweralkyl;

R⁶ and R⁷ are hydrogen independently hydrogen or loweralkyl;

R⁸ and R⁹ are hydrogen independently hydrogen or loweralkyl;

R¹⁰ is hydrogen or loweralkyl; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl, NH₂, —NHC(═NH)NH₂ or aheterocyclic ring having 5 ring atoms and also containing one or twodouble bonds.

Even more highly preferred compounds of the invention are compoundshaving Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrugthereof wherein R¹ is —CO₂H;

—X—R² is R²—C(═O)—NH—, R²—NH—C(═O)—, R²—NH—SO₂— or R²—SO₂—NH— wherein R²is C₁-C₃ loweralkyl or halo-C₁-C₃ loweralkyl;

R⁴ is hydrogen or loweralkyl and R³ is heterocyclic or —Z—R¹⁴ wherein Zand R¹⁴ are defined as above;

R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl, NH₂, —NHC(═NH)NH₂ or aheterocyclic ring having 5 ring atoms and also containing one or twodouble bonds.

Other even more highly preferred compounds of the invention arecompounds having Formula I, IIA, IIB, IIIA or IIIB or a salt, ester orprodrug thereof wherein R¹ is —CO₂H;

—X—R² is R²—C(═O)—NH—, R²—NH—C(═O)—, R²—NH—SO₂— or R²—SO₂NH— wherein R²is C₁-C₃ loweralkyl or halo C₁-C₃ loweralkyl;

R⁴ is hydrogen or loweralkyl and R³ is (a) heterocyclic, (b) alkyl, (b)cycloalkyl, (d) cycloalkylalkyl, (e) alkenyl, (f) alkynyl, (g)—C(═O)—R¹⁴, (h) —C(R^(37a))(OR^(37c))—R¹⁴ or (i)—C(R^(37a))(R^(37b))—N(O)(R^(37c))—R¹⁴ wherein R¹⁴ is

(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v)haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii)cyanoalkyl, (xiv) (R^(37a)O)—(O═)C-substituted alkyl or (xv)(R^(37a)O)₂—P(═O)-substituted alkyl;

R^(37a) and R^(37b) are independently selected from the group consistingof

(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and

R^(37c) is

hydrogen, (ii) loweralkyl or (iii) loweralkenyl;

R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl, NH₂, —NHC(═NH)NH₂ or aheterocyclic ring having 5 ring atoms and also containing one or twodouble bonds.

Most highly preferred compounds of the invention are compounds havingFormula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrug thereofwherein R¹ is —CO₂H;

—X—R² is R²—C(═O)—NH—, R²—NH—C(═O)—, R²—NH—SO₂— or R²—SO₂—NH— wherein R²is C₁-C₃ loweralkyl or halo C₁-C₃ loweralkyl;

R⁴ is hydrogen and R³ is (a) heterocyclic, (b) alkyl or (c)—C(R^(37a))(OR^(37c))—R¹⁴ wherein R¹⁴ is

(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v)haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii)cyanoalkyl, (xiv) (R^(37a)O)—(O═)C-substituted alkyl or (xv)(R^(37a)O)₂—P(═O)-substituted alkyl;

R^(37a) and R^(37b) are independently selected from the group consistingof

(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and

R^(37c) is

hydrogen, (ii) C₁-C₃ loweralkyl or (iii) allyl;

R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl, NH₂, —NHC(═NH)NH₂ or aheterocyclic ring having 5 ring atoms and also containing one or twodouble bonds.

Other most highly preferred compounds of the invention are compoundshaving Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrugthereof wherein R¹ is —CO₂H;

—X—R² is R²—C(═O)—NH— or R²—SO₂—NH— wherein R² is C₁-C₃ loweralkyl orhalo C₁-C₃ loweralkyl;

R⁴ is hydrogen and R³ is (a) heterocyclic, (b) alkyl or (c)—C(R^(37a))(OR^(37c))—R¹⁴ wherein R¹⁴ is

(i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkylor (iv) alkoxy-substituted loweralkyl;

R^(37a) is

(i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and

R^(37c) is

(i) hydrogen, (ii) C₁-C₃ loweralkyl or (iii) allyl;

R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl, NH₂, —NHC(═NH)NH₂ or aheterocyclic ring having 5 ring atoms and also containing one or twodouble bonds.

Other most highly preferred compounds of the invention are compoundshaving Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrugthereof wherein R¹ is —CO₂H;

—X—R² is R²—C(═O)—NH— or R²—SO₂—NH— wherein R² is C₁-C₃ loweralkyl orhalo C₁-C₃ loweralkyl;

R⁴ is hydrogen and R³ is —C(R^(37a))(OR^(37c))—R¹⁴ wherein R¹⁴ isloweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;

R^(37a) is

loweralkyl or loweralkenyl; and

R^(37c) is

hydrogen, C₁-C₃ loweralkyl or allyl;

R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl, C₂-C₅ haloalkenyl, NH₂, —NHC(═NH)NH₂ or aheterocyclic ring having 5 ring atoms and also containing one or twodouble bonds.

Other most highly preferred compounds of the invention are compoundshaving Formula I, IIA, IIB, IIIA or IIIB or a salt, ester or prodrugthereof wherein R¹ is —CO₂H;

—X—R² is R²—C(═O)—NH— or R²—SO₂NH— wherein R² is C₁-C₃ loweralkyl orhalo C₁-C₃ loweralkyl;

R⁴ is hydrogen and R³ is (R^(37a))(OR^(37c))—R¹⁴ wherein R¹⁴ isloweralkyl, loweralkenyl or alkoxy-substituted loweralkyl;

R^(37a) is

loweralkyl or loweralkenyl; and

R^(37c) is

hydrogen, C₁-C₃ loweralkyl or allyl;

R⁵ is hydrogen;

R⁶ and R⁷ are hydrogen;

R⁸ and R⁹ are hydrogen;

R¹⁰ is hydrogen; and

Y is C₂-C₅ alkenyl.

Preferred substituents R¹ include —CO₂H or esters or prodrugs thereof.Preferred esters include C₁-C₆ loweralkyl esters, cycloalkyl esters (forexample, cyclopropyl ester, cyclohexyl ester and the like),cycloalkylalkyl esters, aryl esters (for example, phenyl ester,2-methylphenyl ester and the like), arylalkyl esters (for example,benzyl ester, phenylethyl ester and the like), haloalkyl esters (forexample, 2,2,2-trichloroethyl ester and the like), heterocyclic esters(for example, N-methylpiperazin-4-yl ester and the like),(heterocyclic)alkyl esters (for example, pyridyl methyl ester,pyridylethyl ester, N-methylpiperazin-4-ylmethyl ester,piperidin-1-ylmethyl ester, morpholin-4-ylmethyl ester,2-(piperidin-1-yl)ethyl ester, 2-(morpholin-4-yl)ethyl ester,2(-N-methylpiperazin-4-yl)ethyl ester,1,1-dimethyl-2-(piperidin-1-yl)ethyl ester,1,1-dimethyl-2-(morpholin-4-yl)ethyl ester,1,1-dimethyl-2-(N-methylpiperazin-4-yl)ethyl ester, phthalidylmethylester and the like), di-loweralkylaminoalkyl esters (for example,2-N,N-dimethylaminoethyl ester, 2-N,N-diethylaminoethyl ester and thelike), acyloxyalkyl esters (for example, t-butylcarbonyloxymethyl esterand the like), alkoxycarbonyloxyalkyl esters (for example,t-butyloxycarbonyloxymethyl ester and the like),di-loweralkylaminocarbonylalkyl esters (for example,N,N-dimethylaminocarbonylmethyl ester, N,N-diethylaminocarbonylmethylester and the like), acylalkyl esters (for example,t-butylcarbonylmethyl ester and the like), (heterocyclic)carbonylalkylesters (for example, piperidin-1-ylcarbonylmethyl ester,morpholin-4-ylcarbonylmethyl ester, N-methylpiperazin-4-ylcarbonylmethylester and the like), di-loweralkylaminocarbonyloxyalkyl esters (forexample, N,N-dimthylaminocarbonyloxymethyl ester,N,N-diethylaminocarbonyloxymethyl ester,N-t-butyl-N-methylaminocarbonyloxymethyl ester and the like),alkoxycarbonylalkyl esters (for example, ethoxycarbonylmethyl ester,isopropoxycarbonylmethyl ester and the like),(heterocyclic)carbonyloxyalkyl esters (for example,pyridylcarbonyloxymethyl ester and the like) and the like. Preferredsubstituents R¹ also include —S(O)₂NHC(═O)R¹¹ wherein R¹¹ is defined asabove.

Most highly preferred substituents R¹ include —CO₂H or esters orprodrugs thereof. Most highly preferred esters include C₁-C₆ loweralkylesters, cycloalkyl esters, cycloalkylalkyl esters or substituted orunsubstituted benzyl esters.

Preferred substituents —X—R² include R²—C(═O)—NH—, R²—NH—C(═O)—,R²—NH—SO₂— or R²—SO₂—NH— wherein R² is C₁-C₃ loweralkyl, halo C₁-C₃loweralkyl, C₂-C₃ alkenyl or halo C₂-C₃ alkenyl or —X—R² is

wherein Y¹ is —CH₂—, —O—, —S— or —NH— and Y² is —C(═O)— or—C(R^(aa))(R^(bb))— wherein R^(aa) and R^(bb) are independently selectedfrom the group consisting of hydrogen, C₁-C₃ loweralkyl, hydroxymethyl,1-hydroxyethyl, 2-hydroxyethyl, aminomethyl, 1-aminoethyl, 2-aminoethyl,thiolmethyl, 1-thiolethyl, 2-thiolethyl, methoxymethyl,N-methylaminomethyl and methylthiomethyl.

More preferred substituents —X—R² include R²—C(═O)NH—, R²—NH—C(═O)—,R²—NH—SO₂— or R²—SO₂—NH— wherein R² is C₁-C₃ loweralkyl, halo C₁-C₃loweralkyl, C₂-C₃ alkenyl or halo C₂-C₃ alkenyl or —X—R² is

wherein Y¹ is —CH₂— and Y² is —C(═O)— or —C(R^(aa))(R^(bb))— whereinR^(aa) and R^(bb) are independently selected from the group consistingof hydrogen, C₁-C₃ loweralkyl, hydroxymethyl, 1-hydroxyethyl and2-hydroxyethyl.

Even more preferred substituents —X—R² include R²—C(═O)—NH—,R²—NH—C(═O)—, R²—NH—SO₂— or R²—SO₂—NH— wherein R² is C₁-C₃ loweralkyl,halo C₁-C₃ loweralkyl, C₂-C₃ alkenyl or halo C₂-C₃ alkenyl.

More highly preferred substituents —X—R² include R²—C(═O)—NH—,R²—NH—C(═O)—, R²—NH—SO₂— or R²—SO₂—NH— wherein R² is C₁-C₃ loweralkyl orhalo-C₁-C₃ loweralkyl.

Even more highly preferred substituents —X—R² include R²—C(═O)—NH—,R²—NH—C(═O)—, R²—NH—SO₂— or R²—SO₂—NH— wherein R² is C₁-C₂ loweralkyl orhalo C₁-C₂ loweralkyl, and especially, CH₃—C(═O)—NH—, CF₃—C(═O)—NH—,CH₃—SO₂—NH— or CF₃—SO₂—NH—.

Preferred substituents R³ and R⁴ are independently selected from thegroup consisting of hydrogen, heterocyclic and —Z—R¹⁴ wherein Z and R¹⁴are defined as most broadly defined previously herein and wherein one ofR³ and R⁴ is other than hydrogen.

More highly preferred, substituent R⁴ is hydrogen or loweralkyl and R³includes heterocyclic or —Z—R¹⁴ wherein Z and R¹⁴ are defined as mostbroadly defined previously herein.

Even more highly preferred, substituent R⁴ is hydrogen or loweralkyl andR³ includes

(a) heterocyclic, (b) alkyl, (c) cycloalkyl, (d) cycloalkylalkyl, (e)alkenyl, (f) alkynyl, (g) —C(═O)—R¹⁴, (h) —C(R^(37a))(OR^(37c))—R¹⁴ or(i) —C(R^(37a))(R^(37b))—N(O)(R^(37c))—R¹⁴ wherein R¹⁴ is

(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v)haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii)cyanoalkyl, (xiv) (R^(37a)O)—(O═)C-substituted alkyl or (xv)(R^(37a)O)₂—P(═O)-substituted alkyl;

R^(37a) and R^(37b) are independently selected from the group consistingof

(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and

R^(37c) is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl.

Most highly preferred, substituent R⁴ is hydrogen and R³ includes

(a) heterocyclic, (b) alkyl or (c) —C(R^(37a))(R^(37c))—R¹⁴ wherein R¹⁴is

(i) alkyl, (ii) cycloalkyl, (iii) cycloalkylalkyl, (iv) alkenyl, (v)haloalkyl,

(vi) haloalkenyl, (vii) aryl, (viii) arylalkyl, (ix) heterocyclic,

(x) (heterocyclic)alkyl, (xi) hydroxyalkyl, (xii) alkoxyalkyl, (xiii)cyanoalkyl, (xiv) (R^(37a)O)—(O═)C-substituted alkyl or (xv)(R^(37a)O)₂—P(═O)-substituted alkyl;

R^(37a) and R^(37b) are independently selected from the group consistingof

(i) hydrogen, (ii) loweralkyl and (iii) loweralkenyl; and

R^(37c) is (i) hydrogen, (ii) C₁-C₃ loweralkyl or (iii) allyl.

Also most highly preferred, substituent R⁴ is hydrogen and R³ includes

(a) heterocyclic, (b) alkyl or (c) —C(R^(37a))(OR^(37c))—R¹⁴ wherein R¹⁴is

(i) loweralkyl, (ii) loweralkenyl, (iii) hydroxy-substituted loweralkylor (iv) alkoxy-substituted loweralkyl;

R^(37a) is (i) hydrogen, (ii) loweralkyl or (iii) loweralkenyl; and

R^(37c) is (i) hydrogen, (ii) C₁-C₃ loweralkyl or (iii) allyl.

Also most highly preferred, substituent R⁴ is hydrogen and R³ includes

—C(R^(37a))(OR^(37c))—R¹⁴ wherein R¹⁴ is loweralkyl, loweralkenyl oralkoxy-substituted loweralkyl;

R^(37a) is loweralkyl or loweralkenyl; and

R^(37c) is hydrogen, C₁-C₃ loweralkyl or allyl, and especially, whereinR^(37c) is hydrogen or methyl.

Preferred substituents R⁵ include hydrogen or loweralkyl. Most highlypreferred, R⁵ is hydrogen.

Preferred substituents R⁶ and R⁷ include independently hydrogen andloweralkyl. Most highly preferred, R⁶ and R⁷ are hydrogen.

Preferred substituents R⁸, R⁹ and R¹⁰ include independently hydrogen,fluoro and loweralkyl. Most highly preferred, R⁸, R⁹ and R¹⁰ arehydrogen.

Preferred substituent Y includes C₂-C₅ alkenyl, C₂-C₅ haloalkenyl,—C(═Q²)R²², —N(═Q³), —N(O)═CHCH₃, —NR²³R²⁴ or a heterocyclic ring havingfrom 3 to 6 ring atoms, wherein R²², R²³, R²⁴, Q² and Q³ are defined asabove.

More preferred substituent Y includes C₂-C₅ alkenyl, C₂-C₅ haloalkenyl,—C(═Q²)R²², —N(═Q³), —N(O)═CHCH₃, —NR²³R²⁴ or a heterocyclic ring having5 ring atoms and also containing one or two double bonds, wherein R²²,R²³, R²⁴, Q² and Q³ are defined as above.

Even more preferred substituent Y includes C₂-C₅ alkenyl, C₂-C₅haloalkenyl, NH₂, —NHC(═NH)NH₂ or a heterocyclic ring having 5 ringatoms and also containing one or two double bonds. Representativealkenyl and haloalkenyl substituents Y include:

—CH═CH₂, —CH═CHF, —CH═CH—CH₃, —CH═CH—CF₃, —CH═CHCl, —CH═CHBr, —CH═CF₂,—CH═CF(CH₃), —CH═CF(CF₃), —CH═CFCl, —CH═CFBr, —CH═C(CH₃)₂,—CH═C(CH₃)(CF₃), —CH═CCl(CH₃), —CH═CBr(CH₃), —CH═C(CF₃)₂, —CH═CCl(CF₃),—CH═CBr(CF₃), —CH═CCl₂, —CH═CClBr, —CF═CH₂, —CF═CHF, —CF═CH—CH₃,—CF═CH—CF₃, —CF═CHCl, —CF═CHBr, —CF═CF₂, —CF═CF(CH₃), —CF═CF(CF₃),—CF═CFCl, —CF═CFBr, —CF═C(CH₃)₂, —CF═C(CH₃)(CF₃), —CF═CCl(CH₃),—CF═CBr(CH₃), —CF═C(CF₃)₂, —CF═CCl(CF₃), —CF═CBr(CF₃), —CF═CCl₂,—CF═CClBr, —C(CH₃)═CH₂, —C(CH₃)═CHF, —C(CH₃)═CH—CH₃, —C(CH₃)═CH—CF₃,—C(CH₃)═CHCl, —C(CH₃)═CHBr, —C(CH₃)═CF₂, —C(CH₃)═CF(CH₃),—C(CH₃)═CF(CF₃), —C(CH₃)═CFCl, —C(CH₃)═CFBr, —C(CH₃)═C(CH₃)₂,—C(CH₃)═C(CH₃)(CF₃), —C(CH₃)═CCl(CH₃), —C(CH₃)═CBr(C H₃), —C(CH₃)═C(CF₃)₂, —C(CH₃)═CCl(CF₃), —C(CH₃)═CBr(CF₃), —C(CH₃)═CCl₂,—C(CH₃)═CClBr, —C(CF₃)═CH₂, —C(CF₃)═CHF, —C(CF₃)═CH—CH₃, —C(CF₃)═CH—CF₃,—C(CF₃)═CHCl, —C(CF₃)═CHBr, —C(CF₃)═CF₂, —C(CF₃)═CF(CH₃),—C(CF₃)═CF(CF₃), —C(CF₃)═CFCl, —C(CF₃)═CFBr, —C(CF₃)═C(CH₃)₂,—C(CF₃)═C(CH₃)(CF₃), —C(CF₃)═CCl(CH₃), —C(CF₃)═CBr(CH₃),—C(CF₃)═C(CF₃)₂, —C(CF₃)═CCl(CF₃), —C(CF₃)═CBr(CF₃), —C(CF₃)═CCl₂,—C(CF₃)═CClBr, —CCl═CH₂, —CCl═CHF, —CCl═CH—CH₃, —CCl═CH—CF₃, —CCl═CHCl,—CCl═CHBr, —CCl═CF₂, —CCl═CF(CH₃), —CCl═CF(CF₃), —CCl═CFCl, —CCl═CFBr,—CCl═C(CH₃)₂, —CCl═C(CH₃)(C F₃), —CCl═CCl(CH₃), —CCl═CBr(CH₃),—CCl═C(CF₃)₂, —CCl═CCl(CF₃), —CCl═CBr(CF₃), —CCl═CCl₂, —CCl═CClBr,—CH═CH—CH₂CH₃, —CH═CF—CH₂CH₃, —CF═CH—CH₂CH₃, —CF═CF—CH₂CH₃,—CH═C(CH₃)(CH₂CH₃), —CF═C(CH₃)(CH₂CH₃), —CH═CCl(CH₂CH₃),—CF═CCl(CH₂CH₃), —C(CH₃)═CH—CH₂CH₃, —C(CH₃)═CF—CH₂CH₃, —CCl═CH—CH₂CH₃,—CCl═CF—CH₂CH₃, —C(CH₂CH₃)═CH₂, —C(CH₂CH₃)═CHF, —C(CH₂CH₃)═CF₂,—C(CH₂CH₃)═CH—CH₃, —C(CH₂CH₃)═CF—CH₃, —C(CH₂CH₃)═CH—Cl, —C(CH₂CH₃)═CFCl.

Representative Y substituents which are heterocyclic rings having 5 ringatoms and also containing one or two double bonds include:

furanyl, dihydrofuranyl, didehydrodioxolanyl, dithiolyl, imidazolyl,imidazolinyl, isothiazolyl, isothiazolinyl, isoxazolyl, isoxazolinyl,oxadiazolyl, oxadiazolinyl, oxathiolyl, oxazolyl, oxazolinyl, pyrazolyl,pyrazolinyl, pyrrolyl, dihydropyrrolyl, tetrazolyl, tetrazolinyl,thiadiazolyl, thiadiazolinyl, thiazolyl, thiazolinyl, thienyl,dihydrothienyl, triazolyl, triazolinyl.

More highly preferred substituents Y include cis-propenyl,trans-propenyl, isobutenyl, cis-2-chlorovinyl, vinyl, 2,2-difluorovinyl,imidazolyl, pyrazolyl, oxazolyl, isoxazolyl, thiazolyl, isoxazolyl, NH₂,—NHC(═NH)NH₂.

Most highly preferred substituents Y include cis-propenyl,cis-2-chlorovinyl, vinyl, imidazolyl, pyrazolyl, oxazolyl, isoxazolyl,thiazolyl, isoxazolyl, NH₂, —NHC(═NH)NH₂, especially, cis-propenyl.

Preferred definitions for the substituents in the compounds of theinvention also apply to the intermediates disclosed herein that areuseful in the preparation of the compounds of the invention.

Preferred compounds of the invention include compounds having theindicated relative stereochemistry selected from the group consistingof:

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt;

(±)-(2R,3R,5R,1′R,2′R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(−)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylateAmmonium Salt;

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)butyl-3(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S,3′S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3(cis-propen-1-yl)-pyrrolidine-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen1-yl)-pyrrolidine-5-carboxylic Acid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-(propen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-2-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2S,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-21-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid; and

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Other preferred compounds of the invention include enantiomericallyenriched compounds having the indicated absolute stereochemistryselected from the group consisting of:

(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt;

(2R,3R,5R,1′R,2′R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylateAmmonium Salt;

(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S,3′S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-(propen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R)-2-(1-Acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,l′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-2-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylicAcid;

(2S,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid; and

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

More preferred compounds of the invention include compounds having theindicated relative stereochemistry selected from the group consistingof:

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt;

(±)-(2R,3R,5R,1′R,2′R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(−)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylateAmmonium Salt;

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3R,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S,3′S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-(propen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid; and

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Other more preferred compounds of the invention include enantiomericallyenriched compounds having the indicated absolute stereochemistryselected from the group consisting of:

(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt;

(2R,3R,5R,1′R,2′R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(−)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylateAmmonium Salt;

(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3R,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S,3′S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-(propen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid; and

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Even more preferred compounds of the invention include compounds havingthe indicated relative stereochemistry selected from the groupconsisting of:

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid; and

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Other even more preferred compounds of the invention includeenantiomerically enriched compounds having the indicated absolutestereochemistry selected from the group consisting of:

(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid; and

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

or a pharmaceutically acceptable salt, ester or prodrug thereof.

Most highly preferred compounds of the invention includeenantiomerically enriched esters or prodrugs of compounds having theindicated absolute stereochemistry selected from the group consistingof:

(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-vinyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid; and

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

or a pharmaceutically acceptable salt thereof.

Most highly preferred compounds of the invention also includeenantiomerically enriched esters or prodrugs of the compound having theindicated absolute stereochemistry:

(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid;

or a pharmaceutically acceptable salt thereof.

The term “acid protecting group” as used herein refers to groups used toprotect acid groups (for example, —CO₂H, —SO₃H, —SO₂H, —PO₃H₂, —PO₂Hgroups and the like) against undesirable reactions during syntheticprocedures. Commonly used acid protecting groups are disclosed in T. H.Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2ndedition, John Wiley & Sons, New York (1991) which is incorporated hereinby reference. Most frequently, such acid protecting groups are esters.

Such esters include:

alkyl esters, especially loweralkyl esters, including, but not limitedto, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl,n-pentyl esters and the like;

arylalkyl esters including, but not limited to, benzyl, phenethyl,3-phenylpropyl, naphthylmethyl esters and the like, wherein the arylpart of the arylalkyl group is unsubstituted or substituted aspreviously defined herein;

silylesters, especially, (tri-loweralkyl)silyl esters,(di-loweralkyl)(aryl)silyl esters and (loweralkyl)(di-aryl)silyl esters,including, but not limited to, trimethylsilyl, triethylsilyl,isopropyldimethylsilyl, t-butyldimethylsilyl, methyldiisopropylsilyl,methyldi-t-butylsilyl, triisopropylsilyl, methyldiphenylsilyl,isopropyldiphenylsilyl, butyldiphenylsilyl, phenyldiisopropylsilylesters and the like; and the like.

Preferred acid protecting groups are loweralkyl esters.

The term “activated carboxylic acid group” as used herein refers to acidhalides such as acid chlorides and also refers to activated esterderivatives including, but not limited to, formic and acetic acidderived anhydrides, anhydrides derived from alkoxycarbonyl halides suchas isobutyloxycarbonylchloride and the like, anhydrides derived fromreaction of the carboxylic acid with N,N′-carbonyldiimidazole and thelike, N-hydroxysuccinimide derived esters, N-hydroxyphthalimide derivedesters, N-hydroxybenzotriazole derived esters,N-hydroxy-5-norbornene-2,3-dicarboximide derived esters,2,4,5-trichlorophenol derived esters, p-nitrophenol derived esters,phenol derived esters, pentachlorophenol derived esters,8-hydroxyquinoline derived esters and the like.

The term “acyl” as used herein, refers to groups having the formula—C(═O)—R⁹⁵ wherein R⁹⁵ is hydrogen or an alkyl group. Preferred alkylgroups as R⁹⁵ are loweralkyl groups. Representative examples of acylgroups include groups such as, for example, formyl, acetyl, propionyl,and the like.

The term “acylalkyl” as used herein refers to an acyl group appended toan alkyl radical. Representative examples of acylalkyl groups includeacetylmethyl, acetylethyl, propionylmethyl, propionylethyl and the like.

The term “acylamino” as used herein, refers to groups having the formula—NHR⁸⁹ wherein R⁸⁹ is an acyl group. Representative examples ofacylamino include acetylamino, propionylamino, and the like.

The term “acyloxyalkyl” as used herein refers to an acyloxy group (i.e.,R⁹⁵—C(O)—O— wherein R⁹⁵ is hydrogen or an alkyl group) which is appendedto an alkyl radical. Representative examples of acyloxyalkyl includeacetyloxymethyl, acetyloxyethyl, propioyloxymethyl, propionyloxyethyland the like.

The term “alkenyl” as used herein, refers to a straight or branchedchain hydrocarbon radical containing from 2 to 15 carbon atoms and alsocontaining at least one carbon-carbon double bond. The term “loweralkenyl” refers to straight or branched chain alkenyl radicalscontaining from 2 to 6 carbon atoms. Representative examples of alkenylgroups include groups such as, for example, vinyl, 2-propenyl,2-methyl-1-propenyl, 3-butenyl, 4-pentenyl, 5-hexenyl and the like.

The term “alkenylene” as used herein, refers to a divalent group derivedfrom a straight or branched chain hydrocarbon containing from 2 to 15carbon atoms and also containing at least one carbon-carbon double bond.The term “lower alkenylene” refers to a divalent group derived from astraight or branched chain alkene group having from 2 to 6 carbon atoms.Representative examples of alkenylene groups include groups such as, forexample, —CH═CH—, —CH₂CH═CH—, C(CH₃)═CH—, —CH₂CH═CHCH₂—, and the like.

The term “alkenyloxy” as used herein, refers to groups having theformula —OR⁸¹ where R⁸¹ is an alkenyl group.

The term “alkoxy” as used herein, refers to groups having the formula—OR⁹⁹ wherein R⁹⁹ is an alkyl group. Preferred R⁹⁹ groups are loweralkylgroups. Representative examples of alkoxy groups include groups such as,for example, methoxy, ethoxy, tert-butoxy, and the like.

The term “alkoxyalkoxy” as used herein, refers to groups having theformula —O—R⁹⁶—O—R⁹⁷ wherein R⁹⁷ is loweralkyl, as defined herein, andR⁹⁶ is a lower alkylene group. Representative examples of alkoxyalkoxygroups include groups such as, for example, methoxymethoxy,ethoxymethoxy, t-butoxymethoxy and the like.

The term “alkoxyalkyl” as used herein refers to an alkyl radical towhich is appended an alkoxy group, for example, methoxymethyl,methoxylpropyl and the like.

The term “alkoxycarbonyl” as used herein, refers to groups having theformula, —C(═O)—R⁸⁰, where R⁸⁰ is an alkoxy group.

The term “alkoxycarbonylalkyl” as used herein, refers to groups havingthe formula, —C(═O)—R⁷⁹, appended to the parent molecular moiety throughan alkylene linkage, where R⁷⁹ is an alkoxy group.

The term “alkoxycarbonyloxyalkyl” as used herein refers to analkoxycarbonyloxy group (i.e., R⁸⁰—C(O)—O wherein R⁸⁰ is an alkoxygroup) appended to an alkyl radical. Representative examples ofalkoxycarbonyloxyalkyl include methoxycarbonyloxymethyl,ethoxycarbonyloxymethyl, methoxycarbonyloxyethyl and the like.

As used herein, the term “alkyl” refers to straight or branched chainhydrocarbon radicals containing from 1 to 12 carbon atoms. The term“loweralkyl” refers to straight or branched chain alkyl radicalscontaining from 1 to 6 carbon atoms. Representative examples of alkylgroups include groups such as, for example, methyl, ethyl, n-propyl,isopropyl, n-butyl, iso-butyl, sec-butyl, t-butyl n-pentyl,1-methylbutyl, 2,2-dimethylbutyl, 2-methylpentyl, 2,2-dimethylpropyl,n-hexyl, and the like. The hydrocarbon chains in alkyl groups or thealkyl portion of an alkyl-containing substituent can be optionallyinterrupted by one or two heteroatoms or heterogroups independentlyselected from the group consisting of oxygen, —N(R²⁷)— and sulfurwherein R²⁷ at each occurrence is independently hydrogen, loweralkyl,cylcoalkyl, cycloalkylalkyl or arylalkyl and wherein two suchheteroatoms or heterogroups are separated by at least one carbon atom.

The term “alkylamino” as used herein, refers to groups having theformula —NHR⁹¹ wherein R⁹¹ is an alkyl group. Preferred R⁹¹ groups areloweralkyl groups. Representative examples of alkylamino includemethylamino, ethylamino, and the like.

The term “alkylene” as used herein, refers to a divalent group derivedfrom a straight or branched chain saturated hydrocarbon group havingfrom 1 to 15 carbon. The term “lower alkylene” refers to a divalentgroup derived from a straight or branched chain saturated hydrocarbongroup having from 1 to 6 carbon atoms. Representative examples ofalkylene groups include groups such as, for example, methylene (—CH₂—),1,2-ethylene (—CH₂CH₂—), 1,1-ethylene (—CH(CH₃)—), 1,3-propylene(—CH₂CH₂CH₂—), 2,2-dimethylpropylene (—CH₂C(CH₃)₂CH₂—), and the like.The hydrocarbon chains in alkylene groups or the alkylene portion of analkylene containing substituent can be optionally interrupted by one ortwo heteroatoms or heterogroups independently selected from the groupconsisting of oxygen, —N(R²⁷)— and sulfur wherein R²⁷ at each occurrenceis independently hydrogen, loweralkyl, cylcoalkyl, cycloalkylalkyl orarylalkyl and wherein two such heteroatoms or heterogroups are separatedby at least one carbon atom.

The term “alkylsulfonyl” as used herein refers to the group having theformula, —SO₂—R⁷⁸, where R⁷⁸ is an alkyl group. Preferred groups R⁷⁸ areloweralkyl groups.

The term “alkylsulfonylamino” as used herein refers to the group havingthe formula, —SO₂—R⁷, appended to the parent molecular moiety through anamino linkage (—NH—), where R⁷⁷ is an alkyl group. Preferred groups R⁷⁷are loweralkyl groups.

The term “alkynyl” as used herein, refers to a straight or branchedchain hydrocarbon radical containing from 2 to 15 carbon atoms and alsocontaining at least one carbon-carbon triple bond. The term “loweralkynyl” refers to straight or branched chain alkynyl radicalscontaining from 2 to 6 carbon atoms. Representative examples of alkynylgroups include groups such as, for example, acetylenyl, 1-propynyl,2-propynyl, 3-butynyl, 2-pentynyl, 1-butynyl and the like.

The term “alkynylene” as used herein, refers to a divalent group derivedfrom a straight or branched chain hydrocarbon containing from 2 to 15carbon atoms and also containing at least one carbon-carbon triple bond.The term “lower alkynylene” refers to a divalent group derived from astraight or branched chain alkynylene group from 2 to 6 carbon atoms.Representative examples of alkynylene groups include groups such as, forexample, —C≡C—, —CH₂—C≡C—, —C≡C—CH₂—, —CH(CH₃)—C≡C—, and the like.

The term “aminoalkyl” as used herein refers to an alkyl radical to whichis appended an amino (—NH₂) group.

The term “aryl” as used herein refers to a carbocyclic ring systemhaving 6-10 ring atoms and one or two aromatic rings. Representativeexamples of aryl groups include groups such as, for example, phenyl,naphthyl, tetrahydronaphthyl, indanyl, indenyl and the like.

The aryl groups can be unsubstituted or substituted with one, two orthree substituents, each independently selected from loweralkyl, halo,haloalkyl, haloalkoxy, hydroxy, oxo (═O), hydroxyalkyl, alkenyloxy,alkoxy, alkoxyalkoxy, alkoxycarbonyl, alkoxycarbonylalkyl, thioalkoxy,amino, alkylamino, alkylsulfonyl, dialkylamino, acylamino, unsubstitutedaryl, unsubstituted arylalkyl, unsubstituted arylalkoxy, unsubstitutedaryloxy, mercapto, cyano, nitro, carboxy, carboxaldehyde, NH₂C(═O)—,cycloalkyl, carboxyalkyl, alkylsulfonylamino, unsubstitutedheterocyclic, unsubstituted (heterocyclic)alkyl, unsubstituted(heterocyclic)alkoxy, unsubstituted (heterocyclic)oxy and —SO₃H.Preferred aryl substituents are each independently selected from thegroup consisting of loweralkyl, halo, haloalkyl, hydroxy, hydroxyalkyl,alkenyloxy, alkoxy, alkoxyalkoxy, thioalkoxy, amino, alkylamino,dialkylamino, alkylsulfonyl, acylamino, cyano and nitro. Examples ofsubstituted aryl include 3-chlorophenyl, 3-fluorophenyl, 4-chlorophenyl,4-fluorophenyl, 3,4-dichlorophenyl, 3-chloro-4-fluoro-phenyl,4-methylsulfonylphenyl, and the like.

The term “(aryl)alkenyl” refers to a lower alkenyl group having appendedthereto an aryl group. Representative examples of (aryl)alkenyl groupsinclude groups such as, for example phenylethylenyl, phenylpropenyl, andthe like.

The term “(aryl)alkyl” refers to a loweralkyl group having appendedthereto an aryl group. Representative examples of (aryl)alkyl groupsinclude groups such as, for example benzyl and phenylethyl.

The term “arylalkoxy” as used herein refers to the group having theformula, —O—R⁷⁶ where R⁷⁶ is an arylalkyl group.

The term “(aryl)alkynyl” refers to an alkynylene group having appendedthereto an aryl group. Representative examples of (aryl)alkynyl groupsinclude groups such as, for example phenylacetylenyl, phenylpropynyl,and the like.

The term “aryloxy” as used herein refers to the group having theformula, —O—R⁷², where R⁷² is an aryl group.

The term “carbamoyl” as used herein refers to the group having theformula, —C(═O)—NH₂.

The term “carboxyalkyl” as used herein, refers to the group having theformula, —R⁶⁴—COOH, where R⁶⁴ is a lower alkylene group.

The term “cyanoalkyl” as used herein refers to an alkyl radical to whichis appended a cyano group (—CN).

The term “cycloalkenyl” as used herein refers to an aliphatic ringsystem having 5 to 10 carbon atoms and 1 or 2 rings containing at leastone double bond in the ring structure. Representative examples ofcycloalkenyl groups include groups such as, for example, cyclohexene,cyclopentene, norbornene and the like.

Cycloalkenyl groups can be unsubstituted or substituted with one, two orthree substituents independently selected hydroxy, halo, amino,alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl,mercapto, loweralkenyl and loweralkyl. Preferred substituents areindependently selected from loweralkyl, loweralkenyl, haloalkyl, halo,hydroxy and alkoxy.

The term “(cycloalkenyl)alkenyl” as used herein refers to a cycloalkenylgroup appended to a lower alkenyl radical. Representative examples of(cycloalkenyl)alkenyl groups include groups such as, for example,cyclohexenylethylene, cyclopentenylethylene, and the like.

The term “(cycloalkenyl)alkyl” as used herein refers to a cycloalkenylgroup appended to a lower alkyl radical. Representative examples of(cycloalkenyl)alkyl groups include groups such as, for example,cyclohexenylmethyl, cyclopentenylmethyl, cyclohexenylethyl,cyclopentenylethyl, and the like.

The term “(cycloalkenyl)alkynyl” as used herein refers to a cycloalkenylgroup appended to a lower alkynyl radical. Representative examples of(cycloalkenyl)alkynyl groups include groups such as, for example,cyclohexenylacetylenyl, cyclopentenylpropynyl, and the like.

The term “cycloalkyl” as used herein refers to an aliphatic ring systemhaving 3 to 10 carbon atoms and 1 or 2 rings. Representative cylcoalkylgroups include, for example, cyclopropyl, cyclobutyl, cyclopentyl,cyclohexyl, cycloheptyl, norbornane, bicyclo[2.2.2]octane and the like.

Cycloalkyl groups can be unsubstituted or substituted with one, two orthree substituents independently selected hydroxy, halo, amino,alkylamino, dialkylamino, alkoxy, alkoxyalkoxy, thioalkoxy, haloalkyl,mercapto, loweralkenyl and loweralkyl. Preferred substitutents areindependently selected from loweralkyl, loweralkenyl, haloalkyl, halo,hydroxy and alkoxy.

The term “(cycloalkyl)alkyl” as used herein refers to a cycloalkyl groupappended to a loweralkyl radical. Representative examples of(cycloalkyl)alkyl groups include groups such as, for example,cyclohexylmethyl, cyclopentylmethyl, cyclohexylethyl, cyclopentylethyl,and the like.

The term “(cycloalkyl)alkenyl” as used herein refers to a cycloalkylgroup appended to a lower alkenyl radical. Representative examples of(cycloalkyl)alkenyl groups include groups such as, for example,cyclohexylethylene, cyclopentylethylene, and the like.

The term “(cycloalkyl)alkynyl” as used herein refers to a cycloalkylgroup appended to a lower alkynyl radical. Representative examples of(cycloalkyl)alkynyl groups include groups such as, for example,cyclohexylacetylenyl, cyclopentylpropynyl, and the like.

The term “dialkylamino” as used herein, refers to groups having theformula —N(R⁹⁰)₂ wherein each R⁹⁰ is independently a lower alkyl group.Representative examples of dialkylamino include dimethylamino,diethylamino, N-methyl-N-isopropylamino and the like.

The term “dialkylaminoalkyl” as used herein refers to a dialkylaminogroup appended to an alkyl radical. Representative examples ofdialkylaminoalkyl include dimethylaminomethyl, dimethylaminoethyl,N-methyl-N-ethylaminoethyl and the like.

The term “dialkylaminocarbonylalkyl” as used herein refers to aC(O)—N(R⁹⁰)₂ group (wherein each R⁹⁰ is independently a lower alkylgroup) appended to an alkyl radical. Representative examples ofdialkylaminocarbonylalkyl include dimethylaminocarbonylmethyl,diethylaminocarbonylmethyl, N-methyl-N-ethylaminocarbonylethyl and thelike.

The term “dialkylaminocarbonyloxyalkyl” as used herein refers to a—O—C(O)—N(R⁹⁰)₂ group (wherein each R⁹⁰ is independently a lower alkylgroup) appended to an alkyl radical. Representative examples ofdialkylaminocarbonyloxyalkyl include dimethylaminocarbonyloxymethyl,diethylaminocarbonyloxymethyl, N-methyl-N-ethylaminocarbonyloxyethyl andthe like.

The term “enantiomerically enriched” as used herein refers to a compoundwhich comprises unequal amounts of the enantiomers of an enantiomericpair. In other words, an enantiomerically enriched compound comprisesmore than 50% of one enantiomer of an enantiomeric pair and less than50% of the other enantiomer of the enantiomeric pair. Preferably, acompound that is enantiomerically enriched comprises predominantly oneenantiomer of an enantiomeric pair. Preferably, an enantiomericallyenriched compound comprises greater than 80% of one enantiomer of anenantiomeric pair and less than 20% of the other enantiomer of theenantiomeric pair. More preferably, an enantiomerically enrichedcompound comprises greater than 90% of one enantiomer of an enantiomericpair and less than 10% of the other enantiomer of the enantiomeric pair.Even more preferably, an enantiomerically enriched compound comprisesgreater than 95% of one enantiomer of an enantiomeric pair and less than5% of the other enantiomer of the enantiomeric pair. Even more highlypreferably, an enantiomerically enriched compound comprises greater than97% of one enantiomer of an enantiomeric pair and less than 3% of theother enantiomer of the enantiomeric pair. Yet even more highlypreferably, an enantiomerically enriched compound comprises greater than98% of one enantiomer of an enantiomeric pair and less than 2% of theother enantiomer of the enantiomeric pair. Most preferably, anenantiomerically enriched compound comprises greater than 99% of oneenantiomer of an enantiomeric pair and less than 1% of the otherenantiomer of the enantiomeric pair.

The term “halo” or “halide” as used herein refers to F, Cl, Br or I.

The term “haloalkenyl” as used herein refers to a loweralkenyl group inwhich one or more hydrogen atoms is replaced with a halogen. Examples ofhaloalkenyl groups include 2-fluoroethylene, 1-chloroethylene,1,2-difluoroethylene, trifluoroethylene, 1,1,1-trifluoro-2-propylene andthe like.

The term “haloalkoxy” as used herein refers to the group having theformula, —OR⁶⁹, where R⁶⁹ is a haloalkyl group as defined herein.Examples of haloalkoxy include chloromethoxy, fluoromethoxy,dichloromethoxy, trifluoromethoxy and the like.

The term “haloalkyl” as used herein, refers to a loweralkyl group inwhich one or more hydrogen atoms has been replaced with a halogenincluding, but not limited to, trifluoromethyl, trichloromethyl,difluoromethyl, dichloromethyl, fluoromethyl, chloromethyl, chloroethyl,2,2-dichloroethyl, 2,2,2-trichloroethyl, pentafluoroethyl and the like.

The term “heterocyclic ring” or “heterocyclic” or “heterocycle” as usedherein, refers to any 3- or 4-membered ring containing a heteroatomselected from oxygen, nitrogen and sulfur; or a 5-, 6- or 7-memberedring containing one, two, three, or four nitrogen atoms; one oxygenatom; one sulfur atom; one nitrogen atom and one sulfur atom; twonitrogen atoms and one sulfur atom; one nitrogen atom and one oxygenatom; two nitrogen atoms and one oxygen atom; two oxygen atoms innon-adjacent positions; one oxygen atom and one sulfur atom innon-adjacent positions; or two sulfur atoms in non-adjacent positions.The 5-membered ring has 0-2 double bonds and the 6- and 7-membered ringshave 0-3 double bonds. The nitrogen heteroatoms can be optionallyquaternized. The term “heterocyclic” also includes bicyclic groups inwhich any of the above heterocyclic rings is fused to a benzene ring ora cyclohexane ring or another heterocyclic ring, such as, for example,indolyl, dihydroindolyl, quinolyl, isoquinolyl, tetrahydroquinolyl,tetrahydroisoquinolyl, decahydroquinolyl, decahydroisoquinolyl,benzofuryl, dihydrobenzofuryl or benzothienyl and the like.

Heterocyclic groups include, but are not limited to groups such as, forexample, aziridinyl, azetidinyl, epoxide, oxetanyl, thietanyl, pyrrolyl,pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl,imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, tetrahydropyridyl,piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl,pyridazinyl, oxazolyl, oxazolinyl, oxazolidinyl, isoxazolyl,isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolinyl,thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolinyl,isoquinolinyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, oxetanyl,dihydrofuranyl, tetrahydrofuranyl, dihydropyranyl, tetrahydropyranyl,thienyl, dihydrothienyl, tetrahydrothienyl, triazolyl, triazolinyl,tetrazolyl, tetrazolinyl, isoxazolyl, 1,2,3-oxadiazolyl,1,2,4-oxadiazolyl, 1,3,4-oxadiazolyl, 1,2,5-oxadiazolyl, oxadiazolinyl,1,2,3-thiadiazolyl, 1,2,4-thiadiazolyl, 1,3,4-thiadiazolyl,1,2,5-thiadiazolyl, thiadiazolinyl, 1,3-dithiolinyl, 1,2-dithiolyl,1,3-dithiolyl, 1,3-dioxolinyl, didehydrodioxolanyl, 1,3-oxathiolinyl,oxathiolyl, pyrimidyl, benzothienyl and the like. Heterocyclic groupsalso include compounds of the formula

where X* is —CH₂ or —O— and Y¹ is —C(O)— or [—C(R⁹²)₂—]_(v) where R⁹² ishydrogen or C₁-C₄ alkyl where v is 1, 2, or 3 such as 1,3-benzodioxolyl,1,4-benzodioxanyl and the like. Heterocyclic groups also includebicyclic rings such as quinuclidinyl and the like.

Heterocyclic groups can be unsubstituted or substituted with from one tothree substituents, each independently selected from loweralkyl,hydroxy, alkoxy, thioalkoxy, amino, alkylamino, dialkylamino andhalogen. In addition, nitrogen containing heterocyclic rings can beN-protected.

The term “(heterocyclic)alkenyl” as used herein refers to a heterocyclicgroup appended to a lower alkenyl radical including, but not limited to,pyrrolidinylethenyl, morpholinylethenyl and the like.

The term “(heterocyclic)alkoxy” as used herein refers to the grouphaving the formula, —OR⁶⁸, where R⁶⁸ is a (heterocyclic)alkyl group.

The term “(heterocyclic)alkyl” as used herein refers to a heterocyclicgroup appended to a loweralkyl radical including, but not limited to,pyrrolidinylmethyl, morpholinylmethyl and the like.

The term “(heterocyclic)alkynyl” as used herein refers to a heterocyclicgroup appended to a lower alkynyl radical including, but not limited to,pyrrolidinylacetylenyl, morpholinylpropynyl and the like.

The term “(heterocyclic)carbonylalkyl” as used herein refers to aheterocyclic group appended to an alkyl radical via a carbonyl group.Representative examples of (heterocyclic)carbonylalkyl includepyridylcarbonylmethyl, morpholinocarbonylethyl,piperazinylcarbonylmethyl and the like.

The term “(heterocyclic)carbonyloxyalkyl” as used herein refers to aheterocyclic group appended to an alkyl radical via a carbonyloxy group(i.e., —C(O)—O—). Representative examples of (heterocyclic)carbonylalkylinclude pyridylcarbonylmethyl, morpholinocarbonylethyl,piperazinylcarbonylmethyl and the like.

The term “(heterocyclic)oxy” as used herein refers to a heterocyclicgroup appended to the parent molecular moiety through an oxygen atom(—O—).

The term “hydroxy protecting group”, “hydroxyl protecting group” or “—OHprotecting group” as used herein refers to refers to groups used tohydroxy groups against undesirable reactions during syntheticprocedures. Commonly used hydroxy protecting groups are disclosed in T.H. Greene and P. G. M. Wuts, Protective Groups in Organic Synthesis, 2ndedition, John Wiley & Sons, New York (1991) which is incorporated byreference herein. Such hydroxy protecting groups include:

methyl ether;

substituted methyl ethers, including, but not limited to, methoxymethyl,methylthiomethyl, t-butylthiomethyl, (phenyldimethylsilyl)methoxymethyl,benzyloxymethyl, p-methoxybenzyloxymethyl, (4-methoxyphenoxy)methyl,t-butoxymethyl, 2-methoxyethoxymethyl, 2,2,2-trichloroethoxymethyl,2-(trimethylsilyl)ethoxymethyl, tetrahydropyranyl,tetrahydrothiopyranyl, tetrahydrofuranyl, tetrahydrothiofuranyl etherand the like;

substituted ethyl ethers, including, but not limited to, 1-ethoxyethyl,1-methyl-1-methoxyethyl, 1-methyl-1-benzyloxyethyl,2,2,2-trichloroethyl, trimethylsilylethyl, t-butyl ether and the like;

benzyl ether;

substituted benzyl ethers, including, but not limited to,p-methoxybenzyl, 3,4-dimethoxybenzyl, o-nitorbenzyl, p-halobenzyl,p-cyanobenzyl, diphenylmethyl, triphenylmethyl ether and the like;

silyl ethers, including, but not limited to, trimethylsilyl,triethylsilyl, triisopropylsilyl, dimethylisopropylsilyl,diethylisopropylsilyl, dimethylthexylsilyl, t-butyldimethylsilyl,t-butyldiphenylsilyl, tribenzylsilyl, triphenylsilyl,diphenylmethylsilyl ether and the like;

esters, including, but not limited to, formate, acetate, chloroacetate,dichloroacetate, trichloroacetate, trifluoroacetate, methoxyacetate,phenoxyacetate, pivaloate, benzoate ester and the like; and the like.

Preferred hydroxy protecting groups include substituted methyl ethers,benzyl ether, substituted benzyl ethers, silyl ethers and esters.

The term “hydroxyalkyl” as used herein refers to the group having theformula, —R⁶⁵—OH, where R⁶⁵ is an alkylene group

The term “leaving group” as used herein refers to a group which iseasily displaced from the compound by a nucleophile. Examples of leavinggroups include a halide (for example, Cl, Br or I) or a sulfonate (forexample, mesylate, tosylate, triflate and the like) and the like.

The term “N-protecting group” or “N-protected” as used herein refers tothose groups intended to protect the N-terminus of an amino acid orpeptide or to protect an amino group against undesirable reactionsduring synthetic procedures. Commonly used N-protecting groups aredisclosed in T. H. Greene and P. G. M. Wuts, Protective Groups inOrganic Synthesis, 2nd edition, John Wiley & Sons, New York (1991).N-protecting groups comprise acyl groups such as formyl, acetyl,propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl,trifluoroacetyl, trichloroacetyl, phthalyl, o-nitrophenoxyacetyl,α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, 4-bromobenzoyl,4-nitrobenzoyl, and the like; sulfonyl groups such as benzenesulfonyl,p-toluenesulfonyl and the like; sulfenyl groups such as phenylsulfenyl(phenyl-S—), triphenylmethylsulfenyl (trityl-S—) and the like; sulfinylgroups such as p-methylphenylsulfinyl (p-methylphenyl-S(O)—),t-butylsulfinyl (t-Bu—S(O)—) and the like; carbamate forming groups suchas benzyloxycarbonyl, p-chlorobenzyloxycarbonyl,p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl,2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl,3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl,2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl,2-nitro-4,5-dimethoxybenzyloxycarbonyl,3,4,5-trimethoxybenzyloxycarbonyl,1-(p-biphenylyl)-1-methylethoxycarbonyl,α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, benzhydryloxycarbonyl,t-butyloxycarbonyl, diisopropylmethoxycarbonyl, isopropyloxycarbonyl,ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl,2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitro-phenoxycarbonyl,fluorenyl-9-methoxycarbonyl, cyclopentyloxycarbonyl,adamantyloxycarbonyl, cyclohexyloxycarbonyl, phenylthiocarbonyl and thelike; alkyl groups such as benzyl, p-methoxybenzyl, triphenylmethyl,benzyloxymethyl and the like; p-methoxyphenyl and the like; and silylgroups such as trimethylsilyl and the like. Preferred N-protectinggroups include formyl, acetyl, benzoyl, pivaloyl, t-butylacetyl,phenylsulfonyl, benzyl, t-butyloxycarbonyl (Boc) and benzyloxycarbonyl(Cbz).

The term “thioalkoxy” as used herein refers to groups having the formula—SR⁹⁸ wherein R⁹⁸ is an alkyl group. Preferred groups R⁹⁸ are loweralkylgroups.

The term “thio-substituted alkyl” as used herein refers to an alkylradical to which is appended a thiol group (—SH).

As used herein, the terms “S” and “R” configuration are as defined bythe IUPAC 1974 Recommendations for Section E, FundamentalStereochemistry, Pure Appl. Chem. (1976) 45, 13-30.

The compounds of the invention can comprise asymmetrically substitutedcarbon atoms. As a result, all stereoisomers of the compounds of theinvention are meant to be included in the invention, including racemicmixtures, mixtures of diastereomers, as well as individual opticalisomers, including, enantiomers and single diastereomers of thecompounds of the invention substantially free from their enantiomers orother diastereomers. By “substantially free” is meant greater than about80% free of other enantiomers or diastereomers of the compound, morepreferably greater than about 90% free of other enantiomers ordiastereomers of the compound, even more preferably greater than about95% free of other enantiomers or diastereomers of the compound, evenmore highly preferably greater than about 98% free of other enantiomersor diastereomers of the compound and most preferably greater than about99% free of other enantiomers or diastereomers of the compound.

In addition, compounds comprising the possible geometric isomers ofcarbon-carbon double bonds and carbon-nitrogen double are also meant tobe included in this invention.

Individual stereoisomers of the compounds of this invention can beprepared by any one of a number of methods which are within theknowledge of one of ordinary skill in the art. These methods includestereospecific synthesis, chromatographic separation of diastereomers,chromatographic resolution of enantiomers, conversion of enantiomers inan enantiomeric mixture to diastereomers and then chromatographicallyseparating the diastereomers and regeneration of the individualenantiomers, enzymatic resolution and the like.

Stereospecific synthesis involves the use of appropriate chiral startingmaterials and synthetic reactions which do not cause racemization orinversion of stereochemistry at the chiral centers.

Diastereomeric mixtures of compounds resulting from a synthetic reactioncan often be separated by chromatographic techniques which arewell-known to those of ordinary skill in the art.

Chromatographic resolution of enantiomers can be accomplished on chiralchromatography resins. Chromatography columns containing chiral resinsare commercially available. In practice, the racemate is placed insolution and loaded onto the column containing the chiral stationaryphase. The enantiomers are then separated by HPLC.

Resolution of enantiomers can also be accomplished by converting theenantiomers in the mixture to diastereomers by reaction with chiralauxiliaries. The resulting diastereomers can then be separated by columnchromatography. This technique is especially useful when the compoundsto be separated contain a carboxyl, amino or hydroxyl group that willform a salt or covalent bond with the chiral auxiliary. Chirally pureamino acids, organic carboxylic acids or organosulfonic acids areespecially useful as chiral auxiliaries. Once the diastereomers havebeen separated by chromatography, the individual enantiomers can beregenerated. Frequently, the chiral auxiliary can be recovered and usedagain.

Enzymes, such as esterases, phosphatases and lipases, can be useful forresolution of derivatives of the enantiomers in an enantiomeric mixture.For example, an ester derivative of a carboxyl group in the compounds tobe separated can be prepared. Certain enzymes will selectively hydrolyzeonly one of the enantiomers in the mixture. Then the resultingenantiomerically pure acid can be separated from the unhydrolyzed ester.

In addition, solvates and hydrates of the compounds of Formula I, IIA,IIB, IIIA or IIIB are meant to be included in this invention.

When any variable (for example R¹, R², R³, m, n, etc.) occurs more thanone time in any substituent or in the compound of Formula I, IIA, IIB,IIIA or IIIB or any other formula herein, its definition on eachoccurrence is independent of its definition at every other occurrence.In addition, combinations of substituents are permissible only if suchcombinations result in stable compounds. Stable compounds are compoundswhich can be isolated in a useful degree of purity from a reactionmixture.

This invention is intended to encompass compounds having Formula I, IIA,IIB, IIIA or IIIB when prepared by synthetic processes or by metabolicprocesses. Preparation of the compounds of the invention by metabolicprocesses include those occurring in the human or animal body (in vivo)or processes occurring in vitro.

Compounds of the invention can be prepared according to the methodsdescribed in Schemes 1-10 as shown below.

Throughout the schemes, methods will be illustrated wherein R¹ is acarboxylic acid or carboxylic acid ester substituent. It will beunderstood by those skilled in the art that other R¹ substituents can(a) be obtained either from the carboxylic acid or carboxylic acid estergroup, (b) can be introduced by similar methods to those used tointroduce the carboxylic acid or carboxylic acid ester group or (c) canbe introduced by other methods generally known in the art.

In addition, throughout the schemes, methods will be illustrated whereinR⁴, R⁶, R⁷, R⁸, R⁹ and R¹⁰ are hydrogen. It will be understood by thoseskilled in the art that compounds wherein one or more of thesesubstituents is other than hydrogen can be prepared by methods analogousto those disclosed in the schemes or by other methods generally known inthe art.

In addition, unless otherwise noted, methods will be illustrated forobtaining compounds of the invention having the preferred relativestereochemistry. It will be understood by those skilled in the art thatcompounds of the invention having other relative stereochemistry can beprepared by methods analogous to those disclosed in the schemes or byother methods generally known in the art.

In addition, throughout the schemes, methods will be illustrated whereinX is —C(═O)—NH—. It will be understood by those skilled in the art thatother X groups can be prepared by methods analogous to those disclosedin the schemes or by other methods generally known in the art.

As shown in Scheme 1, reaction of acrolein with an N-protected a-aminoacid ester 1 (P¹ is an N-protecting group, preferably a benzyl group orthe like and P² is a carboxylic acid protecting group, preferably at-butyl group or the like) in an inert solvent (for example, toluene andthe like) in the presence of an acid catalyst (for example, acetic acidand the like), followed by equilibration with a base (for example, withtriethylamine or the like) and separation of the isomers bychromatography, provides substituted pyrrolidine 2. Reduction of thealdehyde group to an alcohol with an aldehyde to alcohol reducing agent(for example, sodium borohydride or the like) in an inert solvent (forexample, methanol or the like), followed by chromatographic separationof the isomers provides alcohol 3. Alcohol 3 can be protected with anhydroxy protecting group P³ (preferably with a silyl protecting group,for example, t-butyldimethylsilyl or the like) using standard alcoholprotection methods to provide 4. Oxidation of the vinyl group ofcompound 4 to an aldehyde is accomplished by reacting compound 4 withOsO₄ and N-methylmorpholine N-oxide to give the corresponding diol. Thediol is then treated with sodium periodate to provide aldehyde 5.Substituents R³ can be introduced via reaction of aldehyde 5 with aGrignard reagent (for example, R³MgBr or the like) to give alcohol 6.Oxidation of alcohol 6 (for example, Swern oxidation or the like)provides ketone 7. Reductive amination of ketone 7 (for example, byreaction with ammonium acetate and sodium cyanoborohydride in methanolor the like) gives amine 8. Amine 8 can be further functionalized tocomplete the introduction of the R²—X— substituent (for example, byreaction of the amine with an acylating agent such as acetic anhydrideor the like or by other acylation methods), followed by chromatographicseparation of the diastereomers to give 9a. The other diastereomericamine (9b) can also be isolated and further transformed according toScheme 1.

Removal of hydroxy protecting group P³ (for example, by reaction with afluoride ion source, such as tetrabutylammonium fluoride or the like,when P³ is a silyl protecting group) provides alcohol 10. Transformationof the hydroxy group of alcohol 10 allows introduction of varioussubstituents Y.

For example, alkylation of the hydroxy group provides ethers 11.N-deprotection (for example, where P¹ is a benzyl group, byhydrogenation) gives 12′, followed by ester hydrolysis (for example,with acid such as HCl), provides compound 12″ of the invention.

Oxidation of the hydroxy group of 10 (for example, Swern oxidation orthe like) provides aldehyde 13. Oxidation of aldehyde 13 (for example,with NaClO₂ or the like) provides carboxylic acid 14. The carboxylicacid substituent of 14 can be used to introduce a variety of otherfunctional groups in substituent Y. For example, the carboxylic acid canbe esterified (for example, by reaction with diazomethane or withethanol and DCC or the like) or the carboxylic acid or an activatedderivative thereof can be reacted with amines to provide 15 (wherein—C(═O)—R²² represents an ester or an amide). N-deprotection (forexample, where P¹ is a benzyl group, by hydrogenation) gives 16′,followed by ester hydrolysis (for example, with acid such as HCl),provides compound 16″ of the invention.

Derivatives of the aldehyde group of 13 or the carboxylic acid group of14 can be used to introduce substituents Y which are —CN or variousheterocycles, according to methods known to those skilled in the art andaccording to the specific methods exemplified herein.

Reaction of aldehyde 13 with loweralkyl- or loweralkenyl-Grignardreagents, followed by oxidation (for example, Swern oxidation or thelike), provides ketones 17 wherein R²² is loweralkyl or loweralkenyl.N-deprotection (for example, where P¹ is a benzyl group, byhydrogenation) gives 18′, followed by ester hydrolysis (for example,with acid such as HCl), provides compound 18″ of the invention.

Compounds wherein substituent Y is an amino group or a derivative of anamino group can be prepared as shown in Scheme 2. Oxidation of aldehyde2 (for example, with AgO or NaClO₂ or the like) provides carboxylic acid19. Curtius rearrangement of carboxylic acid 19 (for example, reactionwith DPPA, Et₃N and benzyl alcohol or the like), followed bychromatographic separation of the diastereomers, provides amide 20wherein P⁴ is an N-protecting group (for example, benzyloxycarbonyl orthe like). Transformations analogous to those which converted compound 4to compound 9a and 9b in Scheme 1, enable the conversion of 20 to 21aand 21b, which can be separated by chromatography. Removal of protectinggroup P⁴ (for example, by selective hydrogenation) provides 22. Furtherderivatization of the amino group allows for introduction ofsubstituents Y which are amine derivatives. N-deprotection (for example,where P¹ is a benzyl group, by hydrogenation), followed by esterhydrolysis (for example, with acid such as HCl), provides compounds ofthe invention wherein Y is amino or an amine derivative.

Olefination of aldehyde 13 (for example, with Ph₃PCH₂ or the like),followed by hydrogenation (causing N-deprotection (for example, where P¹is a benzyl group) and olefin saturation, followed by ester hydrolysis(for example, with acid such as HCl), provides compounds of theinvention wherein Y is loweralkyl.

As shown in Scheme 3, oxidation of the vinyl group of compound 4 to adiol (for example, with OsO₄ and N-methylmorpholine N-oxide or the like)gives diol 23. Removal of N-protecting group P¹ (for example, where P¹is a benzyl group, by hydrogenation) provides pyrrolidine 24.Reprotection with an acid-labile N-protecting group P⁵ (for example,t-butoxycarbonyl or the like) provides 25. Transformation of compound 25to aldehyde 26a and 26b can be accomplished in a manner analogous toconversion of compound 4a to compound 10 and compound 10 to compound 13as shown in Scheme 1. 26a and 26b can be separated by chromatography.

Olefination of 26a (for example, with Ph₃PCH₂, ortriphenylphosine/methylene chloride/n-BuLi, or I⁻Ph₃P⁺CH₂CH₃/KOtBu, orthe like) provides 27 wherein Y is an olefinic substituent.N-deprotection of the P⁵ protecting group and ester hydrolysis, underacidic conditions, provides compounds of the invention 28 wherein Y isan olefinic substituent.

In yet another alternative method shown in Scheme 4, the hydroxy groupof alcohol 3 is protected with a base-labile hydroxy protecting group P⁶(for example, acetyl or the like) to give compound 29. Oxidation of thevinyl group of 29 with OsO₄ and N-methylmorpholine N-oxide provides diol30. Removal of the P¹ protecting group (for example, by hydrogenation orthe like) provides pyrrolidine 31. Reprotection with an acid-labileN-protecting group P⁵ (for example, t-butoxycarbonyl or the like)provides 32. Selective protection of the primary alcohol of 32 with ahydroxy protecting group P⁷ (for example, a silyl protecting group suchas triisopropylsilyl or the like) provides compound 33. Oxidation of 33(for example, Swern oxidation or the like) provides ketone 34. Reductiveamination of ketone 34 (for example, by reaction with ammonium acetateand sodium cyanoborohydride in methanol or the like) gives amine 35.Amine 35 can be further functionalized to complete the introduction ofthe R²—X— substituent (for example, by reaction of the amine with anacylating agent such as acetic anhydride or the like or by otheracylation methods), followed by chromatographic separation of thediastereomers to give 36a. The other diastereomeric amine (36b) can alsobe isolated and further transformed according this scheme.

Selective removal of the P⁶ hydroxy protecting group in 36a (forexample, with K₂CO₃ in methanol or the like) provides alcohol 37.Oxidation of the alcohol to an aldehyde (for example, Swern oxidation orthe like) provides 38. The aldehyde can serve as a precursor for varioussubstituents Y in the compounds of the invention. For example,olefination of 38 (for example, with Ph₃PCH₂, ortriphenylphosine/methylene chloride/n-BuLi, or I⁻Ph₃P⁺CH₂CH₃/KOtBu, orthe like) provides 39 wherein Y is an olefinic substituent. Removal ofthe P⁷ hydroxy protecting group (for example, with a fluoride ion sourcesuch as tetrabutylammonium fluoride or the like) gives alcohol 40.

The alcohol can serve as a precursor for a variety of R³ substituents inthe compounds of the invention. For example, the alcohol of 40 can beoxidized to an aldehyde (for example, by Dess-Martin oxidation or thelike) to give 41. Aldehyde 41 can be reacted with Grignard reagents(R¹⁴MgBr or the like) or other organometallic reagents (for example,organolithium reagents such as R¹⁴Li or the like) to provide 42 as amixture of alcohol diastereomers which can be separatedchromatographically to provide the major isomer 42a and the other isomer42b. Isomer 42a or the mixture of isomers 42 can be oxidized (forexample, by Dess-Martin oxidation or the like) to give ketone 43.Reduction of ketone 43 (for example, with sodium borohydride in ethanolor the like) provides alcohol 42b as the major isomer, which can beisolated by chromatography. N-deprotection of the P⁵ protecting groupand ester hydrolysis, under acidic conditions, provides compounds of theinvention 44a or 44b, respectively, wherein Y is an olefinicsubstituent.

Alkylation of alcohol 42a or 42b provides ethers 45a or 45b,respectively. N-deprotection of the P⁵ protecting group and esterhydrolysis, under acidic conditions, provides compounds of the invention48a or 48b, respectively, wherein Y is an olefinic substituent.

As shown in Scheme 5, reaction of ketone 43 with Grignard reagents(R^(37a)MgBr or the like) or other organometallic reagents (for example,organolithium reagents such as R^(37a)Li or the like) provides alcohols46a and 46b as a mixture of alcohol diastereomers which can be separatedchromatographically. N-deprotection of the P⁵ protecting group and esterhydrolysis, under acidic conditions, provides compounds of the invention47a or 47b, respectively, wherein Y is an olefinic substituent.

Alkylation of alcohol 46a or 46b provides ethers 49a or 49b,respectively. N-deprotection of the P⁵ protecting group and esterhydrolysis, under acidic conditions, provides compounds of the invention50a or 50b, respectively, wherein Y is an olefinic substituent.

Esters or prodrugs of the compounds of the invention can be prepared bymethods known in the art.

Scheme 6 illustrates a method for preparing enantiomerically enrichedcompounds of the invention having the preferred absolutestereochemistry. Protected pyrrole 51 (wherein P⁸ is an N-protectinggroup, for example, t-butyloxycarbonyl or the like, and P⁹ is a hydroxyprotecting group, for example, t-butyldimethylsilyl or the like; J. Org.Chem. 57 3760-3763 (1992)) is reacted with imine 52 (wherein P¹⁰ is anN-protecting group, for example, p-toluenesulfinyl (—S(O)Tol),t-butylsulfinyl (—S(O)-t-Bu), tritylsulfenyl ((Ph)₃C—S—), phenylsulfenyl(Ph-S—), p-methoxyphenyl, p-methoxybenzyl or the like and wherein anyfunctional groups within group R³ that require protection areappropriately protected) in the presence of a Lewis acid, for example,trimethylsilyltriflate, borontrifluoride etherate or the like, in aninert solvent, for example, dichloromethane or the like, to provideunsaturated lactam 53 Preferably, N-protecting groups P⁸ and P¹⁰ can beselectively deprotected/removed in the presence of each other. Reactionof 53 with an organometallic reagent Y—M (wherein M is a metal), forexample, a cuprate reagent or the like, in an inert solvent, forexample, THF or the like, provides substituted lactam 54. Lactam 54 isconverted to cyano-substituted pyrrolidine 55, for example, by (i)reduction with a lactam reducing agent, for example, diisobutylaluminumhydride or the like, in an inert solvent, for example, THF or the like,followed by (ii) treatment with methanol and a catalytic amount of anacid, for example, pyridinium p-toluenesulfonic acid or the like,followed by (iii) reaction with a cyanide source, for example,trimethylsilylcyanide or the like, in an inert solvent, for example,dichloromethane or the like. Alternatively, lactam 54 is converted tocyano-substituted pyrrolidine 55, for example, by (i) reduction with alactam reducing agent, for example, diisobutylaluminum hydride or thelike, in an inert solvent, for example, THF or the like, followed by(ii) reaction with a cyanide source, for example, trimethylsilylcyanideor the like, in an inert solvent, for example, dichloromethane or thelike in the presence of a Lewis acid such as trimethylsilyl triflate orthe like. Removal of protecting group P¹⁰ (for example, with an acidsuch as trifluoroacetic acid, pyridinium p-toluenesulfonic acid or thelike in a suitable solvent), followed by reaction of the amine with anacylating agent such as acetic anhydride or the like or by otheracylation methods gives 56. Hydrolysis of the nitrile of 56 and removalof protecting group P⁸, for example, with hydrochloric acid or the like,and deprotection of any protected functional groups within group R³provides carboxylic acid 57. Esters or prodrugs of 57 can be prepared bymethods known in the art.

Among the preferred compounds of the invention are compounds such as 58or esters or prodrugs thereof wherein R^(37a), R^(37c) and R¹⁴ are asdefined most broadly herein. Especially preferred are compounds 58 oresters or prodrugs thereof wherein R^(37a) is loweralkyl orloweralkenyl, R^(37c) is hydrogen, C₁-C₃ loweralkyl or allyl and R¹⁴ isloweralkyl, loweralkenyl or alkoxy-substituted loweralkyl. In thosecases where R^(37c) is hydrogen, the hydroxy group will be protectedthroughout the process of Scheme 6. Compound 58 can be preparedaccording to the process described in Scheme 6 by first reacting 51 withimine 59.

The N-protected imine 52 is prepared by reaction of the correspondingaldehyde with P¹⁰NH₂.

Scheme 7 illustrates a method for preparing preferred imines 59. Allylicalcohol 60 (wherein R^(14a) and the carbon to which it is bonded, whentaken together, will become substituent R¹⁴) is asymmetricallyepoxidized, for example, by Sharpless epoxidation with t-butylhydroperoxide, (−)-dimethyl D-tartrate and titanium tetraisopropoxide orthe like in an inert solvent such as dichloromethane and the like andthe alcohol is protected (for example, P¹¹ is benzoate or the like) togive 61. Epoxide 61 is reduced, for example, with lithium aluminumhydride or the like in an inert solvent such as THF or the like,followed by protection of the primary alcohol of 62 (for example, P¹² isbenzyl or the like) to give 63. Where R^(37c) is other than hydrogen, 63is reacted with a non-nucleophilic strong base, for example, sodiumbis(trimethylsilyl)amide or the like, and R^(37c)—X wherein X is ahalide or other leaving group in an inert solvent such as THF or thelike to provide 64. Where R^(37c) is hydrogen, the hydroxy group isprotected. Protecting group P¹² is removed, preferably, selectively ifany other hydroxy protecting groups are present in the compound, forexample, by hydrogenation when it is a benzyl group, and the resultingalcohol is oxidized to an aldehyde, for example, with pyridiniumchlorochromate or the like to give aldehyde 65. Reaction of 65 withP¹⁰NH₂ gives 59.

An alternative method for preparation of enantiomerically enrichedcompounds of the invention having the preferred absolute stereochemistryis shown in Scheme 8. Unsaturated lactam 66 (Tetrahedron Asymmetry1167-1180 (1996)) wherein P¹³ is an N-protecting group, for example,t-butyloxycarbonyl or the like, and P¹⁴ is a hydroxy protecting group,for example, t-butyldimethylsilyl or the like, is reacted with anorganometallic reagent Y—M (wherein M is a metal), for example, acuprate reagent or the like, in an inert solvent, for example, THF orthe like, to provide 67. Lactam 67 is converted to cyano-substitutedpyrrolidine 68, for example, by (i) reduction with a lactam reducingagent, for example, diisobutylaluminum hydride or the like, in an inertsolvent, for example, THF or the like, followed by (ii) treatment withmethanol and a catalytic amount of an acid, for example, pyridiniump-toluenesulfonic acid or the like, followed by (iii) reaction with acyanide source, for example, trimethylsilylcyanide or the like, in aninert solvent, for example, dichloromethane or the like. Deprotection ofthe alcohol (for example, with a fluoride ion source such astetrabutylammonium fluoride or the like when P¹⁴ is a silyl basedhydroxy protecting group), followed by conversion of the alcohol to anazide group (for example, by reaction with triphenylphosphine, diethyldiazodicarboxylate and diphenylphosphory azide or the like in an inertsolvent such as THF or the like) provides 69. The azide is reduced (forexample, with triphenylphosphine in THF/water or the like), theresulting amine is acylated (for example, with an acylating agent suchas acetic anhydride or the like or by other acylation methods) and thediol is deprotected (for example, with acetic acid or the like) to give70. Diol 70 is oxidized to the aldehyde 71, for example, with sodiummetaperiodate or the like. The aldehyde 71 can be converted to 72 bymethods described in Schemes 4 and 5. Compound 72 can be converted to 57according to the method described in Scheme 6 for converting 56 to 57.

More particularly, compounds 58 wherein R^(37a) is loweralkyl orloweralkenyl, R^(37c) is hydrogen, C₁-C₃ loweralkyl or allyl and R¹⁴ isloweralkyl, loweralkenyl or alkoxy-substituted loweralkyl are preparedfrom 71 according to the methods outlined in Schemes 4 and 5 to give 73,which is converted to 58. In those cases where R^(37c) is hydrogen, thehydroxy group will be protected throughout the process of Scheme 8.

Another alternative method for preparation of enantiomerically enrichedcompounds of the invention having the preferred absolute stereochemistryis shown in Scheme 9. Aldehyde 74 (wherein P¹⁵ is an N-protecting group,for example, t-butyloxycarbonyl or the like and, preferably, whereinR^(37a) is loweralkyl or loweralkenyl, R^(37c) is hydrogen, C₁-C₃loweralkyl or allyl and R¹⁴ is loweralkyl, loweralkenyl oralkoxy-substituted loweralkyl) is reacted with N-protected hydroxylamineP¹⁶—NHOH wherein P¹⁶ is an N-protecting group, for example,p-methoxybenzyl or the like, to provide nitrone 75. Preferably,N-protecting groups P¹⁵ and P¹⁶ can be selectively deprotected/removedin the presence of each other. The carbanion of a carboxy protectedpropiolate is prepared by reacting the carboxy protected propiolate (P¹⁷is an acid protecting group, for example, methyl or t-butyl or the like)with a non-nucleophilic strong base, for example, n-BuLi or the like inan inert solvent, for example, THF or the like. The propiolate carbanionis then reacted with nitrone 75 to give 76. Reaction of 76 with zincdust in acetic acid/methanol provides unsaturated lactam 77. Unsaturatedlactam 77 is reacted with an organometallic reagent Y—M (wherein M is ametal), for example, a cuprate reagent or the like, in an inert solvent,for example, THF or the like, to provide 78. Removal of protecting groupP¹⁵ (for example, with an acid such as trifluoroacetic acid, pyridiniump-toluenesulfonic acid or the like in a suitable solvent), followed byreaction of the amine with an acylating agent such as acetic anhydrideor the like or by other acylation methods gives 79. Optionally,N-protecting group P¹⁶ can be replaced by another N-protecting groupbefore completing the process (for example, where P¹⁶ is p-methoxybenzylor the like it can be removed and replaced with t-butyloxycarbonyl orthe like). Lactam 79 is converted to cyano-substituted pyrrolidine 80,for example, by (i) reduction with a lactam reducing agent, for example,diisobutylaluminum hydride or the like, in an inert solvent, forexample, THF or the like, followed by (ii) treatment with methanol and acatalytic amount of an acid, for example, pyridinium p-toluenesulfonicacid or the like, followed by (iii) reaction with a cyanide source, forexample, trimethylsilylcyanide or the like, in an inert solvent, forexample, dichloromethane or the like. Hydrolysis of the nitrile of 80and removal of protecting group P¹⁶, for example, with hydrochloric acidor the like, provides carboxylic acid 58. In those cases where R^(37c)is hydrogen, the hydroxy group will be protected throughout the processof Scheme 9. Esters or prodrugs of 58 can be prepared by methods knownin the art.

Compound 74 can be prepared according to the process shown in Scheme 10.In Scheme 10, P¹⁵ is exemplified by t-butyloxycarbonyl (Boc), but can beother N-protecting groups. Compound 81 is prepared from D-serineaccording to Campbell, et al., Synthesis 1707 (1998). Reaction of 81with an organometallic reagent R¹⁴—M wherein M is a metal (for example,a Grignard reagent (R¹⁴—MgCl or R¹⁴—MgBr or the like) in an inertsolvent, for example, THF or the like, provides 82. Ketone 82 is reactedwith an organometallic reagent R^(37a)—M wherein M is a metal (forexample, a Grignard reagent, R^(37a)—MgCl or R^(37a)—MgBr or the like)in an inert solvent, for example, THF or the like, to provide 83, whereR^(37c) is other than hydrogen, 83 is reacted with a non-nucleophilicstrong base (for example, sodium hydride or the like) in an inertsolvent such as THF or the like, followed by reaction with R^(37c)—Xwhere X is a leaving group such as a halide or the like to provide 84.Where R^(37c) is hydrogen, the hydroxy group is suitably protected.Deprotection of 84, for example, with p-toluenesulfonic acid in methanolor the like, provides 85. Oxidation of 85, for example, with pyridinesulfur trioxide complex, DMSO and pyridine or the like, gives aldehyde86, which corresponds to 74 wherein P¹⁵ is t-butyloxycarbonyl.

The other compounds of the invention can be readily prepared from thecompounds described herein using techniques known in the chemicalliterature. The methods required are known and can be readily practicedby those having ordinary skill in the art.

Key intermediates for the preparation of compounds of the inventioninclude the following.

wherein P¹ is an N-protecting group (preferably, a benzyl group or asubstituted benzyl group) and P² is a carboxylic acid protecting group(preferrably, a loweralkyl group, especially t-butyl); preferrably, P¹and P² can be selectively deprotected/removed; or a salt thereof;

wherein P¹ is an N-protecting group (preferably, a benzyl group or asubstituted benzyl group) and P² is a carboxylic acid protecting group(preferably, a loweralkyl group, especially t-butyl); and P³ is hydrogenor a hydroxy protecting group (preferably, an acyl protecting group, forexample, acetyl and the like, or a silyl protecting group, for example,t-butyldimethylsilyl and the like); preferrably, P¹, P² and P³ can beselectively deprotected/removed; or a salt thereof;

wherein P¹ is an N-protecting group (preferably, a benzyl group or asubstituted benzyl group) and P² is a carboxylic acid protecting group(preferably, a loweralkyl group, especially t-butyl); and P⁴ is hydrogenor an N-protecting group (preferably, a carbamate N-protecting group,for example, benzyloxycarbonyl and the like); preferrably, P¹, P² and P⁴can be selectively deprotected/removed; or a salt thereof;

wherein P⁵ is an N-protecting group (preferably, an acid labileN-protecting group, such as t-butyloxycarbonyl and the like) and P² is acarboxylic acid protecting group (preferably, a loweralkyl group,especially t-butyl); and P⁶ is hydrogen or a hydroxy protecting group(preferably, a base labile hydroxy protecting group, such as acetyl andthe like); and P⁷ is hydroxy protecting group (preferably, a silylprotecting group, such as triisopropylsilyl and the like); preferrably,P², P⁵, P⁶ and P⁷ can be selectively deprotected/removed; or a saltthereof; and

wherein P⁵ is an N-protecting group (preferably, an acid labileN-protecting group, such as t-butyloxycarbonyl and the like) and P² is acarboxylic acid protecting group (preferably, a loweralkyl group,especially t-butyl); and P⁶ is hydrogen or a hydroxy protecting group(preferably, a base labile hydroxy protecting group, such as acetyl andthe like); and P⁷ is hydroxy protecting group (preferably, a silylprotecting group, such as triisopropylsilyl and the like); and R² isdefined as herein (preferably, loweralkyl or haloloweralkyl; mostpreferably, methyl or trifluoromethyl); preferrably, P², P⁵, P⁶ and P⁷can be selectively deprotected/removed; or a salt thereof.

Other key intermediates for the preparation of compounds of theinvention include compounds, including mixtures of compounds having theindicated relative stereochemistry or enantiomerically enrichedcompounds having the indicated absolute stereochemistry, of the formula(6)-(17).

wherein P⁸ is an N-protecting group (including, t-butyloxycarbonyl orthe like), P¹⁰ is an N-protecting group (including, p-toluenesulfinyl(—S(O)Tol), t-butylsulfinyl (—S(O)-t-Bu), tritylsulfenyl ((Ph)₃C—S—),phenylsulfenyl (Ph-S—), p-methoxyphenyl, p-methoxybenzyl or the like)and R³ is defined as above (both in terms of its broadest definition andin terms of each of the preferred embodiments); or a salt thereof. Inaddition, any functional groups in substituent R³ can be suitablyprotected. Most highly preferred is substituent R³ of the formula:

wherein R^(37a), R^(37c) and R¹⁴ are as defined above (both in terms oftheir broadest definitions and in terms of each of their preferredembodiments). Especially preferred are compounds wherein R³⁷, isloweralkyl or loweralkenyl, R^(37c) is hydrogen, C₁-C₃ loweralkyl orallyl and R¹⁴ is loweralkyl, loweralkenyl or alkoxy-substitutedloweralkyl. In those cases where R^(37c) is hydrogen, the hydroxy groupcan be protected with a hydroxy protecting group. Preferably, P⁸ and P¹⁰can be selectively deprotected/removed.

wherein P⁸, P¹⁰ and R³ are defined as in (6) above and wherein Y isdefined as above (both in terms of its broadest definition and in termsof each of the preferred embodiments); or a salt thereof.

wherein P⁸, P¹⁰, R³ and Y are defined as in (7) above; or a saltthereof.

wherein P⁸, R³ and Y are defined as in (7) above and R² is defined asabove (both in terms of its broadest definition and in terms of each ofthe preferred embodiments); or a salt thereof.

wherein P¹⁰, R¹⁴, R^(37a) and R^(37c) are as defined in (6) above; or asalt thereof.

wherein R¹⁴, R^(37a) and R^(37c) are as defined in (6) above; or a saltthereof.

wherein R¹⁴, R^(37a) and R^(37c) are as defined in (6) above, R² is asdefined in (9) above and P¹³ is an N-protecting group (including,t-butyloxycarbonyl or the like); or a salt thereof.

wherein R¹⁴, R^(37a) and R^(37c) are as defined in (6) above and P¹⁵ isan N-protecting group (including, t-butyloxycarbonyl or the like); or asalt thereof.

wherein R¹⁴, R^(37a), R^(37c) and P¹⁵ are as defined in (13) above andP¹⁶ is an N-protecting group (including, p-methoxybenzyl or the like):or a salt thereof. Preferably, P¹⁵ and P¹⁶ can be selectivelydeprotected/removed.

wherein R¹⁴, R^(37a), R^(37c) P¹⁵ and P¹⁶ are as defined in (14) aboveand P¹⁷ is an acid protecting group (including, methyl or t-butyl or thelike); or a salt thereof.

wherein R¹⁴, R^(37a), R^(37c) and P¹⁶ are as defined in (14) above andR² is as defined in (9) above; or a salt thereof.

wherein R¹⁴, R^(37a), R^(37c), P¹⁶ and R² are as defined in (16) above;or a salt thereof.

The reagents required for the synthesis of the compounds of theinvention are readily available from a number of commercial sources suchas Aldrich Chemical Co. (Milwaukee, Wis., USA); Sigma Chemical Co. (St.Louis, Mo., USA); and Fluka Chemical Corp. (Ronkonkoma, N.Y., USA); AlfaAesar (Ward Hill, Mass. 01835-9953); Eastman Chemical Company(Rochester, N.Y. 14652-3512); Lancaster Synthesis Inc. (Windham, N.H.03087-9977); Spectrum Chemical Manufacturing Corp. (Janssen Chemical)(New Brunswick, N.J. 08901); Pfaltz and Bauer (Waterbury, Conn. 06708).Compounds which are not commercially available can be prepared byemploying known methods from the chemical literature.

The following examples will serve to further illustrate the preparationof the compounds of the invention, without limitation.

EXAMPLE 1(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicAcid Hydrochloride

1A. (±)-(2S,3R,5R)- and(±)-(2S,3S,5R)-1-Benzyl-2-vinyl-3-formyl-pyrrolidine-5-carboxylic Acidt-Butyl Ester (8.1 ratio).

Acrolein (8 mL, 120 mmole) was added to a solution of t-butylN-benzyl-glycinate (4.34 g, 19.6 mmole) and acetic acid (5 drops) intoluene (100 mL). The solution was heated at reflux. After 1 hour, thereaction was cooled to about 50° C. and an additional 3 mL of acroleinwere added. The reaction was heated at reflux for an additional 2 hoursand concentrated in vacuo. The residue was purified by chromatography onsilica gel using 5% ethyl acetate/hexanes to provide a mixture of(±)-(2S,3R,5R)- and(±)-(2S,3S,5R)-1-benzyl-2-vinyl-3-formylpyrrolidine-carboxylic acidt-butyl esters as an oil (yield: 2.78 g, 45%). The mixture of aldehydeswas equilibrated to an 8:1 ratio by stirring the crude product withtriethylamine (0.5 mL) in ethyl acetate at room temperature followed byevaporation of the solvents.

¹H NMR (CDCl₃) (major isomer only): δ 1.45 (s, 9H), 2.26 (m, 1H), 2.69(m, 1H), 3.49 (dd, J=7.8, 3.0 Hz, 1H), 3.61 (d, J=13.5 Hz, 1H), 3.93 (m,1H), 3.94 (d, J=13.5 Hz, 1H), 5.22-5.33 (two dd, 2H), 5.7 (ddd, J=17.7,10.2, 7.8 Hz, 1H), 7.21-7.35 (m, 5H), 9.71 (d, J=1.2 Hz, 1H).

MS (M+H)⁺=316.

1B.(±)-(2S,3R,5R)-1-Benzyl-2-vinyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of the 8:1 mixture of (±)-(2S,3R,5R)- and(±)-(2S,3S,5R)-1-benzyl-2-vinyl-3-formylpyrrolidine-5-carboxylic acidt-butyl ester (6.0 g, 19.0 mmole), prepared according to the methoddescribed in Example 1A, in 100 mL of methanol was cooled to 0° C. andtreated with sodium borohydride (0.72 g, 19.0 mmole). The mixture wasstirred for 0.5 hour, warmed to room temperature, and stirred for anadditional 1 hour. The reaction was quenched with aqueous ammoniumchloride, and the solvent was evaporated. The residue was partitionedbetween ethyl acetate and water. The organic layer was dried over MgSO₄,filtered and concentrated in vacuo. The residual oil was purified bychromatography on silica gel using a gradient of 20-30% ethylacetate/hexanes to furnish the title compound as a colorless oil (yield:4.0 g, 66%).

¹H NMR (CDCl₃): δ 1.46 (s, 9H), 1.80 (m, 1H), 2.16 (m, 1H), 2.39 (m,1H), 2.54 (m, 1H), 3.48-3.53 (m, 2H), 3.08 (d, 2H), 3.91 (d, 2H),5.17-5.22 (m, 2H), 5.70 (m, 1H), 7.23-7.34 (m, 5H).

MS (M+H)⁺=318.

1C.(±)-(2S,3R,5R)-1-Benzyl-2-vinyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (3.6 g, 11.4 mmole), tert-butyldimethylsilyl chloride(3.7 g, 24.5 mmole) and imidazole (2.8 g, 41.2 mmole) in 80 mL of DMFwas stirred at room temperature for 1.5 hours. The reaction was dilutedwith ethyl acetate, washed with water and brine, dried over MgSO₄, andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 5% ethyl acetate/hexanes to provide the title compound,as a colorless oil (yield: 3.5 g, 71%).

¹H NMR (CDCl₃): δ 0.02 (d, 6H), 0.86 (s, 9H), 1.43 (s, 9H), 1.67 (ddd,1H), 2.11 (m, 1H), 2.28 (m, 1H), 3.40-3.70 (m, 6H), 3.90 (d, 2H),5.11-5.19 (m, 2H), 5.69 (ddd, 1H), 7.20-7.30 (m, 5H).

MS (M+H)⁺=432.

1D.(±)-(2R,3R,5R)-1-Benzyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

Osmium tetroxide (20 mg) was added to a room temperature solution of(±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (3.5 g, 8.12 mmole) in 60 mL of 8:1 acetone/water andN-methylmorpholine N-oxide (3.0 g, 25.6 mmole). The reaction mixture wasstirred at room temperature for 6 hours and quenched with saturatedaqueous Na₂S₂O₃. The mixture was stirred for an additional 10 minutesand the solvent removed. The brownish residue was partitioned betweendichloromethane and water. The organic layer was dried over MgSO₄ andconcentrated in vacuo to provide the intermediate diol as an oil (˜3.8 g) which was used without additional purification.

MS (crude): (M+H)⁺=466.

The crude diol was dissolved in 6:1 tetrahydrofuran (THF)/water (50 mL)and treated with sodium periodate (3.0 g, 14.0 mmole). The mixture wasstirred at room temperature for 1 hour and diluted with ethyl acetate,washed with water, dried over MgSO₄, filtered, and concentrated invacuo. The crude aldehyde was purified by chromatography on silica gelusing 3% ethyl acetate/hexanes to provide the title compound as acolorless oil (yield: 1.6 g, 46%).

¹H NMR (CDCl₃): δ 0.03 (d, 6H), 0.86 (s, 9H), 1.46 (s, 9H), 1.72 (m,1H), 2.26-2.45 (m, 2H), 3.53-3.71 (m, 5H), 3.84 (d, 1H), 3.93 (d, 1H),7.27-7.31 (m, 5H), 9.32 (d, 1H).

MS (M+H)⁺=434.

1E.(±)-(2R,3R,5R)-1-Benzyl-2-(1-oxo-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A dry flask containing magnesium (0.14 g, 5.83 mmole), under argon, wascharged with 10 mL of dry THF and 3 drops of dibromoethane. This wasfollowed by addition of 1-bromo-2-ethylbutane (0.95 g, 5.83 mmole). Thereaction mixture was heated at reflux for 45 minutes, until most of themagnesium had reacted. The reaction mixture was cooled to −30° C. and(±)-(2R,3R,5R)-1-benzyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (0.5 g, 1.15 mmole) in of THF (6 mL) was added,dropwise. The reaction was slowly warmed to −10° C., over a period ofabout 2 hours, and quenched with aqueous ammonium chloride. Theresultant slurry was diluted with ethyl acetate and washed with water,brine, and dried over MgSO₄ and concentrated. The crude alcohol product,an oil (0.85 g), was used without further purification.

MS (M+H)⁺=520.

A solution of oxalyl chloride (2.5 mL, 2M in CH₂Cl₂) in 10 mL ofanhydrous dichloromethane was prepared and maintained under a nitrogenatmosphere, at −78° C. DMSO (0.77 mL, 9.83 mmole) was added slowly tothe solution. The mixture was stirred for 15 minutes and treated withthe crude alcohol prepared above, about 0.85 g, in 5 mL of anhydrousdichloromethane. The solution was stirred for 1 hour and triethylamine(2.3 mL, 16.4 mmole) was added slowly to the reaction mixture. Thesolution was then allowed to slowly warmed to room temperature anddiluted with dichloromethane. The organic layer was washed with water,dried over MgSO₄, and concentrated. The residue was purified bychromatography on silica gel using 3% ethyl acetate/hexanes to providethe title compound, as an oil (yield: 0.35 g, 66%).

MS (M+H)⁺=518.

1F. (±)-(2R,3R,5R,1′R)- and(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-amino-3-ethyl)-pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (0.20 g, 0.39 mmole), ammonium acetate (30 equiv.)and sodium cyanoborohydride (10 equiv.) in 5 mL of methanol was heatedat reflux for 24 hours with occasional addition of an additional 60equivalents of ammonium acetate and 20 equivalents of sodiumcyanoborohydride. The solvent was evaporated. The resultant residue waspartitioned between dichloromethane and water. The organic layer wasdried over MgSO₄, filtered, and concentrated. The product was purifiedby chromatography on silica gel using 30-50% ethyl acetate/hexanes toprovide the title compound as a colorless oil (yield: 130 mg, 64%).

¹H NMR (CDCl₃) δ 7.30 (m, 5H), 4.91 (s, 1H), 3.53 (m, 2H), 3.08 (m, 1H),2.88 (m, 1H), 2.35 (m, 1H), 1.85 (m, 1H), 1.44 (s, 9H), 1.20-1.40 (m,7H), 0.88 (s, 9H), 0.85 (m, 6H), 0.03 (s, 6H).

MS (M+H)⁺=519.

1G.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of (±)-(2R,3R,5R,1′R)- and(+)-(2R,3R,5R,1′S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (110 mg, 0.21 mmole) and acetic anhydride (214 mg,2.1 mmole) in 10 mL of dichloromethane was stirred for 1 hour. Thesolvent and excess acetic anhydride were removed in vacuo. The residuewas purified by chromatography on silica gel using 30% ethylacetate/hexanes to provide the title compound as a white solid (yield:85 mg, 72%).

¹H NMR (CDCl₃) δ 7.28 (m, 5H), 5.14 (d, J=14 Hz, 1H), 4.36 (m, 1H), 3.95(m, 2H), 3.62 (m, 1H), 3.52 (m, 1H), 3.45 (m, 1H), 2.98 (m, 1H), 1.98(s, 3H), 1.60 (m, 2H), 1.43 (s, 9H), 1.20-1.40 (m, 7H), 0.88 (s, 9H),0.80 (m, 6H), 0.04 (s, 6H).

MS (M+H)⁺=561.

1H.(1)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (85 mg, 0.15 mmole) in dry THF (5 mL) was preparedand maintained at room temperature under a nitrogen atmosphere.Tetrabutylammonium fluoride (1M in THF, 0.23 mL) was added slowly to thesolution. The reaction mixture was stirred for 1 hour. The solvent wasremoved in vacuo and the residue purified by chromatography on silicagel using 30-50% ethyl acetate/hexanes to provide the title compound asa white foam (yield: 41 mg, 61%).

¹H NMR (CDCl₃) δ 7.20-7.35 (m, 5H), 5.20 (d, J=14 Hz, 1H), 4.28 (m, 1H),4.93 (m, 2H), 3.65 (m, 2H), 3.50 (m, 1H), 3.23 (m, 2H), 2.22 (m, 2H),1.98 (s, 3H), 1.62 (m, 1H), 1.43 (s, 9H), 1.15-1.40 (m, 7H), 0.80 (m,6H).

MS (M+H)⁺=447.

1I.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(methoxy-methyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A mixture of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (40 mg, 0.09 mmole) and silver oxide (200 mg, 0.90mmole) in 3 mL of iodomethane was heated at reflux for three hours. Thereaction was cooled, filtered, and the solvent was removed in vacuo, toprovide the title product as a crude oil.

MS (M+H)⁺=461.

1J.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A mixture of the crude(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethylpyrrolidine-5-carboxylicacid t-butyl ester (32 mg, 0.07 mmole), prepared according to the methoddescribed in Example 1I, and ammonium formate (130 mg, 2.1 mmole) inethanol (5 mL) was heated at reflux in the presence of a catalyticamount of 10% palladium, on activated carbon, for 1.5 hours. Thereaction was filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel using 50% ethyl acetate/hexanesfollowed by 10% methanol/dichloromethane to provide the title compoundas a colorless oil (yield: 16 mg, 47%).

MS (M+H)⁺=371.

1K.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicAcid Hydrochloride.

A solution of the(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (15 mg) was dissolved in 6 N HCl in water (1 mL) andstirred at room temperature for 3 hours. The solvent was removed underhigh vacuum to provide the title compound as a white solid.

¹H NMR (d₆-DMSO) δ 8.10 (d, J=14 Hz, 1H), 4.28 (m, 1H), 4.18 (m, 1H),3.45 (m, 1H), 3.22 (s, 3H), 2.47 (m, 1H), 2.38 (m, 1H), 1.90 (m, 1H),1.88 (s, 3H), 1.15-1.42 (m, 7H), 0.82 (t, J=12.5 Hz, 3H), 0.79 (t,J=12.5 Hz, 3H).

MS (M+H)⁺=315, (M−H)⁻=313.

EXAMPLE 2(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid Hydrochloride

2A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of oxalyl chloride (0.11 mL, 2M in CH₂Cl₂) in 5 mL ofanhydrous dichloromethane was prepared and maintained, under a nitrogenatmosphere, at −78° C. DMSO (32 mg, 0.42 mmole) was added slowly to thesolution. The mixture was stirred for 15 minutes and treated with(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (38 mg, 0.085 mmole) in 5 mL of dichloromethane. Thesolution was stirred for 1 hour and triethylamine (86 mg, 0.85 mmole)was added slowly to the reaction mixture. The solution was allowed towarm to room temperature and diluted with dichloromethane. The organiclayer was washed with water and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica gelusing 3% ethyl acetate/hexanes to provide the title compound as acolorless oil (yield: 39 mg, 97%).

¹H NMR (CDCl₃) δ 9.68 (d, J=1.0 Hz, 1H), 7.28 (m, 5H), 5.06 (d, J=14 Hz,1H), 4.38 (m, 1H), 4.10 (m, 1H), 3.75 (m, 2H), 3.45 (m, 1H), 2.62 (m,1H), 2.20 (m, 2H), 1.98 (s, 3H), 1.42 (s, 9H), 1.25-1.40 (m, 7H), 0.82(m, 6H).

MS (M+H)⁺=445.

2B.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of NaClO₂ (0.16 g) and NaH₂PO₄.H₂O (0.17 g) in water (1 mL)was added to a solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (35 mg, 0.079 mmole) and 2-methyl-2-butene (0.5 mL)dissolved in t-BuOH (1.5 mL) and acetonitrile (1.5 mL) at 0° C. After 1hour the reaction was quenched with 10% aqueous Na₂S₂O₃ and extractedwith dichloromethane. The organic layer was washed with water and brine,dried (MgSO₄) and concentrated to provide the title product (yield: ˜30mg).

MS (M+H)⁺=461.

2C.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of Diazald™ (0.5 g, 2.33 mmole) in 5 mL of ether was addedslowly to a solution of aqueous KOH (0.5 g in 1 mL of water) and 1 mL ofethanol maintained at 65° C. Diazomethane was distilled into a receivingflask charged with a solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester (30 mg, 0.065 mmole) in 3 mL of THF. The receivingflask was cooled to 0° C. in an ice/water bath. The condenser was cooledwith dry ice/acetone and 3 mL of ether was added the distilling flaskuntil the distillate was colorless. The reaction was stirred for anadditional 0.5 hours at 0° C. The yellowish reaction mixture wasquenched with acetic acid (0.1 mL) and diluted with ethyl acetate. Theorganic layer was washed with 10% NaHCO₃ and brine, dried with MgSO₄ andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 50% ethyl acetate/hexanes to provide the title compoundas a colorless oil (yield: 20 mg, 65%).

¹H NMR (CDCl₃) δ 7.25 (m, 5H), 5.10 (d, J=14 Hz, 1H), 4.23 (m, 1H), 4.08(m, 1H), 3.85 (m, 1H), 3.72 (m, 1H), 3.69 (s, 3H), 3.40 (m, 1H), 2.75(m, 1H), 2.33 (m, 1H), 2.15 (m, 1H), 1.98 (s, 3H), 1.42 (s, 9H),1.20-1.40 (m, 7H), 0.83 (m, 6H).

MS (M+H)⁺=475.

2D.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A mixture of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester (14 mg, 0.03 mmole) and ammonium formate (0.3 g) inethanol (1.5 mL) with a catalytic amount of 10% palladium on activatedcarbon was heated at about 75° C., for 1 hour. After filtration toremove the catalyst, the solvent was removed in vacuo. The residue waspurified by chromatography on silica gel to provide the title compoundas a colorless oil (yield: 8.5 mg, 73%).

MS (M+H)⁺=385.

2E.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid Hydrochloride.

A solution of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonylpyrrolidine-5-carboxylicacid t-butyl ester (8.5 mg, 0.022 mmole) in 4 N HCl in dioxane (1 mL)was stirred at room temperature for 24 hours. The solvent was removed invacuo to provide the title compound as an off-white solid (yield 8 mg,100%).

¹H NMR (d₆-DMSO) δ 8.02 (d, J=14 Hz, 1H), 4.40 (m, 1H), 4.22 (m, 1H),3.85 (t, J=13 Hz, 1H), 3.70 (m, 1H), 3.65 (s, 3H), 3.15 (m, 1H), 2.55(m, 1H), 2.20 (m, 1H), 1.84 (s, 3H), 1.12-1.42 (m, 7H), 0.82 (t, J=12.5Hz, 3H), 0.68 (t, 3H).

MS (M+H)⁺=329, (M−H)⁻=327.

EXAMPLE 3(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid Hydrochloride

3A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(hydroxyiminoformyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared by reacting a solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester with hydroxylamine hydrochloride and 10% aqueouspotassium carbonate in methanol according to the procedure described byChelucci et al., Tetrahedron: Asymmetry 5:1973 (1994).

3B.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared by reacting a solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(hydroxyiminoformyl)-pyrrolidine-5-carboxylicacid t-butyl ester with 1,1′-carbonyldiimidazole in dichloromethaneaccording to the procedure described by Chelucci et al., Tetrahedron:Asymmetry 5:1973 (1994).

3C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

3D.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound is prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 4(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine-5-carboxylicAcid Hydrochloride

4A. (±)-(2R,3R,5R,1′S,1″R)- and(±)-(2R,3R,5R,1′S,1″S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(1-hydroxy)propyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

Ethyl magnesium bromide (0.070 mL, 3M in ether) was added to a solutionof(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (18 mg, 0.041 mmole) in 3 mL of tetrahydrofuran. Thereaction mixture was maintained at 0° C., and stirred for 1 hour. Thereaction was quenched with aqueous ammonium chloride and partitionedbetween ethyl acetate and water. The organic layer was dried over MgSO₄,filtered and concentrated to provide the title product (crude yield: 20mg, 100%).

MS (M+H)⁺=475.

4B.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 2A, substituting (±)-(2R,3R,5R,1′S,1′R)- and(±)-(2R,3R,5R,1′S,1″S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(1-hydroxy)propyl-pyrrolidine-5-carboxylicacid t-butyl ester, 20 mg, 0.041 mmole), in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 11 mg, 56%).

MS (M+H)⁺=473.

4C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A mixture of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine-5-carboxylicacid t-butyl ester (11 mg, 0.023 mmole), ammonium formate (250 mg) andpalladium (15 mg, 10% on carbon) in ethanol (1.5 mL) was heated at 70°C. for 20 minutes. The reaction was filtered, to remove the catalyst andconcentrated. The residue was purified by chromatography on silica gelusing 5% methanol/chloroform to provide the title compound (yield: 8.5mg, 95%).

MS (M+H)⁺=383.

4D.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine-5-carboxylicAcid Hydrochloride.

A solution of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine-5-carboxylicacid t-butyl ester (8 mg) was dissolved in 4 N HCl in dioxane (1 mL) andstirred at room temperature for 24 hours. The reaction was concentratedin vacuo to provide the title compound as an off white solid (yield: 8mg, 100%).

¹H NMR (DMSO-d₆) δ 8.03 (d, J=14 Hz, 1H), 4.41 (m, 1H), 4.20 (m, 1H),3.92 (m, 1H), 3.68 (m, 1H), 3.46 (m, 1H), 2.65 (m, 2H), 2.00 (m, 1H),1.84 (s, 3H), 1.10-1.35 (m, 9H), 0.95 (t, J=Hz, 3H), 0.81 (t, J=12.5 Hz,3H), 0.75 (t, J=12.5 Hz, 3H).

MS: (M−H)⁻=325, (M+35)⁺=361, (2M−H)⁻=651; (M+H)⁺=327, (2M+1)⁺=653,(2M+Na)⁺=675.

EXAMPLE 5(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-methylcarbamoyl)-pyrrolidine-5-carboxylicAcid Hydrochloride

5A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N-methylcarbamoyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester (0.175 mmole) and triethylamine (18 mg, 0.175 mmole)in 10 mL THF was cooled in an ice-bath. Isobutylchloroformate (24 mg,0.175 mmole) was added and stirred for 30 min. Then methylamine (2.0 Min THF, 0.35 mL, 0.70 mmole) was added. The mixture was stirred whileallowed to warm up to room temperature overnight. The reaction was thendiluted with ethyl acetate. The organic layer was washed with water,andbrine, dried over MgSO₄, filtered and concentrated in vacuo. The residuewas purified by chromatography on silica gel using 5% methanol/methylenechloride to provide the title compound, as an oil (yield: 17.2 mg, 21%).

MS: (M+H)⁺=474.

5B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-methylcarbamoyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N-methylcarbamoyl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 13 mg, 94%).

MS: (M+H)⁺=384.

5C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-methylcarbamoyl)-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(N-methylcarbamoyl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (D₂O): δ 4.43 (t, J=10 Hz, 1H), 4.36 (m, 1H), 4.09 (dd, 1H), 3.08(q, J=10 Hz, 1H), 2.75 (m, 4H), 2.25 (m, 4H), 2.02 (s, 3H), 1.5-1.15(br, 7H), 0.80 (m, 6H).

MS: (M+H)⁺=328.

EXAMPLE 6(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-aminocarbamoyl)-pyrrolidine-5-carboxylicAcid Hydrochloride

6A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N-(t-butoxycarbonyl)aminocarbamoyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester (60 mg, 0.13 mmole), t-butyl carbamate (21 mg, 0.16mmole), 1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride(EDC, 31 mg, 0.16 mmole) and 1-hydroxybenzotriazole (9 mg, 0.065 mmole)in 3 mL anhydrous THF was stirred at room temperature for 6 hours. Thereaction was then diluted with ethyl acetate. The organic layer waswashed with water and brine, dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by chromatography on silica gel using2% methanol/methylene chloride to provide the title compound, as an oil(yield: 45.6 mg, 61%).

MS: (M+H)⁺=575.

6B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-(t-butoxycarbonyl)aminocarbamoyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N-(t-butoxycarbonyl)aminocarbamoyl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S))-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 28 mg, 75%).

MS: (M+H)⁺=484.

6C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-aminocarbamoyl)-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(N-(t-butoxycarbonyl)aminocarbamoyl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (D₂O): δ 4.32 (m, 2H), 4.18 (dd, 1H), 3.14 (q, J=8.4 Hz, 1H),2.75 (m, 1H), 2.26 (m, 1H), 2.01 (s, 3H), 1.50-1.15 (m, 7H), 0.80 (q,J=7.5 Hz, 6H).

MS: (M+H)⁺=329.

EXAMPLE 7(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylicAcid Hydrochloride

7A. (±)-(2R,3R,5R,1′S)1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester (42 mg, 0.091 mmole), ethanol (0.5 mL),1-(3-dimethylaminopropyl)-3-ethylcarbodiimide hydrochloride (EDC, 36 mg,0.188 mmole) and 1-hydroxybenzotriazole (7 mg, 0.05 mmole) in 2 mLanhydrous THF was stirred at room temperature overnight. The reactionwas then diluted with ethyl acetate. The organic layer was washed withwater, and brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel using 2%methanol/methylene chloride to provide the title compound, as an oil(yield: 36 mg, 33%).

¹H NMR (CDCl₃): δ 7.50-7.20 (br, 5H), 5.12 (d, J=9 Hz, 1H), 4.60-4.30(br, 2H), 4.14 (q, J=6 Hz, 2H), 4.08 (m, 1H), 3.85 (br, 1H), 3.72 (m,1H), 3.40 (m, 1H), 2.75 (m, 1H), 2.32 (m, 1H), 1.97 (s, 3H), 1.40 (s,9H), 1.37 (t, J=6 Hz, 3H), 1.20-1.50 (m, 7H), 0.83 (m, 6H).

Mass spectrum: (M+H)⁺=489.

7B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

Mass spectrum: (M+H)⁺=399.

7C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 2E, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (D₂O): δ 4.35 (m, 1H), 4.20 (q, J=7.5 Hz, 2H), 3.87-3.55 (m, 2H),3.20 (q, J=7.5 Hz, 1H), 2.67 (m, 1H), 2.42 (m, 1H), 2.02 (s, 3H), 1.24(t, J=7.5 Hz, 3H), 1.54-1.15 (m, 7H), 0.82 (m, 6 H).

Mass spectrum: (M+H)⁺=343, (M−H)⁻=341.

EXAMPLE 8(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetyl-pyrrolidine-5-carboxylicAcid Hydrochloride

8A. (±)-(2R,3R,5R,1′S,1″R)- and(±)-(2R,3R,5R,1′S,1″S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(1-hydroxy)ethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 4A substituting methyl magnesium bromide in place of ethylmagnesium bromide.

8B.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-acetyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 2A, substituting (±)-(2R,3R,5R,1′S,1″R)- and(±)-(2R,3R,5R,1′S,1″S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(1-hydroxy)ethyl-pyrrolidine-5-carboxylicacid t-butyl ester, prepared according to the procedure described inExample 8A, in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (CDCl₃) δ 5.00 (d, J=9.7 Hz, 1H), 3.94 (m, 2H), 3.68 (m, 1H),3.55 (m, 1H), 2.64 (m, 1H), 2.32 (m, 1H), 2.29 (s, 3H), 2.20 (m, 1H),1.94 (s, 3H), 1.43 (s, 9H), 1.15-11.35 (m, 7H), 0.80 (m, 6H).

MS: (M+H)⁺=459.

8C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 4C, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-acetyl-pyrrolidine-5-carboxylicAcid t-butyl ester, prepared according to the procedure described inExample 8B, in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-propionyl-pyrrolidine-5-carboxylicacid t-butyl ester.

MS: (M+H)⁺=369.

8D.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetyl-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound is prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-acetyl-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆) δ 8.20 (m, 1H), 4.35 (m, 1H), 4.15 (m, 1H), 4.03 (m,1H), 2.43 (m, 1H), 2.03 (m, 1H), 1.91 (s, 3H), 1.77 (s, 3H), 1.55 (m,1H), 1.46 (m, 1H), 1.35 (m, 2H), 1.12 (m, 4H), 0.84 (m, 3H), 0.79 (m,3H).

MS: (M+H)⁺=314, (M−H)⁻=312.

EXAMPLE 9(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5-carboxylicAcid Dihydrochloride

9A. (±)-(2S,3R,5R)- and(±)-(2S,3S,5R)-1-Benzyl-2-vinyl-3-carboxyl-pyrrolidine-5-carboxylic Acidt-Butyl Ester.

A solution of (±)-(2S,3R,5R)- and(±)-(2S,3S,5R)-1-benzyl-2-vinyl-3-formyl-pyrrolidine-5-carboxylic acidt-butyl ester (10 g, 31.7 mmole) (8:1 ratio), in 39 mL of ethanol wasprepared. The solution was treated with a suspension of silver oxide(8.83 g, 38.1 mmole) and potassium hydroxide (10.86 g, 194 mmole) in 65mL of water. The reaction was stirred at room temperature for 1 hour andfiltered through a pad of Celite®. The ethanol was removed in vacuo. Theaqueous solution was acidified with acetic acid to about pH 4. Theacidic solution was extracted with ethyl acetate. The organic layer waswashed with brine, dried over Na₂SO₄, filtered and concentrated toprovide the title compound as a brownish oil (crude yield: 8.2 g, 77%).The crude acid was used for the next step without further purification.

MS (M+H)⁺=332, (M−H)⁻=330.

9B.(±)-(2S,3R,5R)-1-Benzyl-2-vinyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A mixture of (±)-(2S,3R,5R)- and(±)-(2S,3S,5R)-1-benzyl-2-vinyl-3-carboxylpyrrolidine-5-carboxylic acidt-butyl ester (1.0 g, 3.02 mmole), diphenylphosphoryl azide (0.83 g,3.32 mmole), benzyl alcohol (0.36 g, 4.53 mmole) and triethylamine (0.32g, 3.32 mmole) in 30 mL of toluene was heated at reflux for 16 hours.The solvent was evaporated and the residue was purified bychromatography on silica gel using 10% ethyl acetate/hexanes to providethe title compound as a colorless oil (yield: 0.86 g, 65%).

¹H NMR (CDCl₃) δ 7.20-7.40 (m, 10H), 5.70 (m, 2H), 5.10-5.23 (m, 3H),4.10 (m, 1H), 3.85 (m, 1H), 3.62 (m, 1H), 3.45 (m, 2H), 2.50 (m, 1H),1.70 (m, 1H), 1.41 (s, 9H).

MS (M+H)⁺=437.

9C.(±)-(2R,3R,5R)-1-Benzyl-2-formyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

Osmium tetroxide (3 crystals) was added to a stirred solution of the(±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester (1.10 g, 2.52 mmole), N-methylmorpholine N-oxide(0.95 g, 8.07 mmole), in 27 mL of acetone/water (8:1), maintained atroom temperature. After 6 hours, 10% aqueous Na₂S₂O₃ was added andstirring continued for an additional 15 minutes. The reaction wasextracted with dichloromethane and the organic layer was concentrated toprovide the crude diol intermediate. The diol product was used in thenext step without additional purification.

MS (M+H)⁺=471.

Sodium periodate (1.0 g, 4.52 mmole) was added in portions to a stirredsolution of the crude diol (˜1.25 g, 2.66 mmole) in 21 mL of THF/water(6:1). The reaction was stirred for 1 hour then diluted with ethylacetate. The organic layer was washed with water and brine, dried overMgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel using 15% ethyl acetate/hexanes to providethe title compound as a colorless oil (yield: 0.66 g, 60%).

¹H NMR (CDCl₃) δ 9.44 (d, J=1.2 Hz, 1H), 7.20-7.40 (m, 10H), 5.98 (d,J=14 Hz, 1H), 5.10 (m, 2H), 4.45 (m, 1H), 3.90 (m, 2H), 3.70 (m, 1H),3.60 (m, 1H), 2.43 (m, 1H), 1.70 (m, 1H), 1.45 (s, 9H).

MS (M+H)⁺=439.

9D. (±)-(2R,3R,5R,1′R)- and(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-hydroxy-3-ethyl)pentyl-3-benzyloxycarbonylaminopyrrolidine-5-carboxylicAcid t-Butyl Ester.

1-Bromo-2-ethylbutane (1.7 g, 10.3 mmole) was added a solution ofdibromoethane (3 drops) in 15 mL of dry THF, under argon, in a flaskcharged with magnesium (0.25 g, 10.3 mmole). The reaction mixture washeated at reflux for 45 minutes, until most of the magnesium reacted.The solution was allowed to cool to room temperature and transferred viacannula to a suspension of CuBr.SMe₂ (2.12 g, 10.3 mmole) in 15 mL ofdry THF, maintained under argon, at −10° C. The mixture was stirred for0.5 hours until the solution turned dark. A solution of(±)-(2R,3R,5R)-1-benzyl-2-formyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester (0.45 g, 1.03 mmole) in 10 mL of THF was addeddropwise and stirred for 1.5 hours, while maintaining the temperature at0° C. The reaction was quenched with aqueous ammonium chloride, dilutedwith ethyl acetate, washed with water and brine, dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography onsilica gel using 10% ethyl acetate/hexanes to provide alcohol adducts asa pale yellow oil (yield: 160 mg, 30%).

¹H NMR (CDCl₃) δ 7.20-7.40 (m, 10H), 6.10 (d, J=14 Hz, 1H), 5.10 (m,2H), 4.22 (m, 1H), 4.01 (m, 1H), 3.71 (m, 1H), 3.65 (m, 2H), 3.55 (m,1H), 3.20 (m, 1H), 2.00-2.30 (m, 2H), 1.45 (s, 9H), 1.15-1.40 (m, 7H),0.84 (m, 6H).

MS (M+H)⁺=525.

9E.(±)-(2R,3R,5R)-1-Benzyl-2-(1-oxo-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of oxalyl chloride (0.29 ml, 2 M in CH₂Cl₂) in 5 mL of drydichloromethane was prepared and maintained under a nitrogen atmosphereat −78° C. DMSO (90 mg, 1.14 mmole) was added to the solution. Themixture was stirred for 15 minutes. The alcohol adduct, prepared above,(150 mg, 0.286 mmole), in 5 mL of dichloromethane, was added dropwise tothe cold (−78° C.) reaction mixture. The solution was stirred, at −78°C., for 1 hour. Triethylamine (250 mg, 2.29 mmole) was added slowly. Thereaction was allowed to slowly warm to room temperature and then dilutedwith dichloromethane. The organic layer was washed with water and brine,dried over MgSO₄, filtered and concentrated. The residue was purified bychromatography on silica gel using 5% ethyl acetate/hexanes to providethe title compound (yield: 100 mg, 67%).

¹H NMR (CDCl₃) δ 7.35 (m, 10H), 5.10 (m, 2H), 4.28 (m, 1H), 3.95 (m,2H), 2.60 (m, 1H), 2.40 (m, 1H), 2.03 (m, 1H), 1.70 (m, 2H), 1.45 (s,9H), 1.10-1.30 (m, 7H), 0.70 (m, 6H).

MS (M+H)⁺=523.

9F. (±)-(2S,3R,5R,1′R)- and(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-amino-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A mixture of(±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester (90 mg, 0.172 mmole), ammonium acetate (400 mg, 5.17mmole) and sodium cyanoborohydride (65 mg, 1.03 mmole) in 5 mL inmethanol was heated at reflux for 18 hours. Additional portions ofammonium acetate and sodium cyanoborohydride were added and heatingcontinued for an additional 2 hours. The reaction was quenched with 1 Nsodium hydroxide, and diluted with dichloromethane. The organic layerwas washed with water and brine, dried over MgSO₄, filtered andconcentrated. The residue was purified by chromatography on silica gelusing 1:1 ethyl acetate/hexanes followed by 5% methanol/dichloromethaneto provide the title compounds. (yield: 58 mg, 64%).

MS (M+H)⁺=524.

9G. (±)-(2S,3R,5R,1′R)- and(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of (±)-(2S,3R,5R,1′R)- and(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester (50 mg, 0.096 mmole) and acetic anhydride (117 mg,1.15 mmole) in 5 mL of dichloromethane was stirred for 1 hour at roomtemperature. The solvent was evaporated in vacuo and the residuepurified by chromatography on silica gel using 30-50% ethylacetate/hexanes to provide the title compound as a colorless oil (yield:51 mg, 97%).

¹H NMR (CDCl₃) δ 7.72-7.35 (m, 10H), 5.82 (d, J=14 Hz, 1H), 5.10 (m,2H), 4.38 (m, 1H), 4.15 (m, 2H), 3.63 (m, 1H), 3.38 (m, 1H), 3.10 (m,1H), 2.15 (m, 1H), 2.00 (s, 3H), 1.65 (m, 1H), 1.42 (s, 9H), 1.20-1.35(m, 7H), 0.80 (m, 6H).

MS (M+H)⁺=567.

9H.(±)-(2S,3R,5R,1′S)-2-(1-Acetamidoethyl)pentyl-3-amino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of (±)-(2S,3R,5R,1′R)- and(+)-(2S,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester (49 mg, 0.087 mmole), ammonium formate (150 mg, 0.22mmole) and 10% palladium on activated carbon in ethanol (5 mL) washeated at 80° C. for 45 minutes. After filtration to remove thecatalyst, the solvent was removed. The residue was purified bychromatography on silica gel using 5-10% methanol/dichloromethane tofurnish the diastereomers, (±)-(2S,3R,5R,1′S) (19 mg) and(±)-(2S,3R,5R,1′R) (8.6 mg) of2-(1-acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5-carboxylic acidt-butyl ester.

¹H NMR (CDCl₃) δ 6.00 (d, J=14 Hz, 1H), 3.90 (m, 1H), 3.73 (m, 1H), 3.49(m, 1H), 3.10 (m, 1H), 2.48 (m, 1H), 2.03 (s, 3H), 1.82 (m, 1H), 1.48(s, 9H), 1.15-1.42 (m, 7H), 0.85 (m, 6H).

MS (M+H)⁺=342.

9I.(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5-carboxylicAcid Dihydrochloride.

A solution of(±)-(2S,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5-carboxylicacid t-butyl ester (17 mg, 0.050 mmole) in 1 mL of 6 N HCl was stirredat room temperature for 3 hours. The solvent was removed under highvacuum to provide the title compound as a white solid (yield: 15 mg,100%).

¹H NMR (d₆-DMSO) δ 8.28 (bs, 1H), 7.90 (d, J=Hz, 1H), 4.71 (d, J=14 Hz,1H), 4.39 (m, 1H), 4.10 (m, 1H), 3.92 (m, 1H), 3.08 (m, 1H), 2.64 (m,1H), 2.31 (m, 1H), 1.95 (m, 1H), 1.88 (s, 3H), 1.50 (m, 1H), 1.10-1.40(m, 7H), 0.72-0.90 (m, 6H).

MS (M+H)⁺=286.

EXAMPLE 10(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetamido-pyrrolidine-5-carboxylicAcid Hydrochloride

10A.(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester (50 mg, 0.88 mmole) was stirred with 10% palladium oncarbon (5 mg) in 50 mL of ethyl acetate under 1 atmosphere of hydrogenfor 45 minutes. The reaction was filtered and concentrated to providethe title compound as an oil (crude yield: 35 mg, 92%).

MS (M+H)⁺=431.

10B.(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-acetamido-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5-carboxylicacid t-butyl ester (35 mg, 0.080 mmole) was reacted with aceticanhydride (0.05 mL) in 8 mL of dichloromethane for 1 hour. The reactionwas concentrated and the residue purified by chromatography on silicagel using 50% ethyl acetate/hexanes followed by 3%methanol/dichloromethane to provide the title compound (yield: 30 mg,80%).

¹H NMR (CDCl₃) δ 7.20-7.35 (m, 5H), 6.62 (d, J=14 Hz, 1H), 5.34 (d, J=14Hz, 1H), 4.42 (m, 2H), 4.20 (m, 1H), 3.68 (m, 1H), 3.42 (m, 1H), 3.10(m, 1H), 2.18 (m, 2H), 2.02 (s, 3H), 1.96 (s, 3H), 1.45 (s, 9H),1.25-1.42 (m, 7H), 0.85 (m, 6H).

MS (M+H)⁺=474.

10C.(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetamido-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-acetamido-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester. The residue was purified by chromatography on silicagel using 5% methanol/dichloromethane to provide the title compound(yield: 11.5 mg, 50%).

¹H NMR (CDCl₃) δ 6.20 (d, J=14 Hz, 1H), 5.94 (d, J=14 Hz, 1H), 4.24 (m,1H), 4.08 (m, 1H), 3.95 (m, 1H), 3.75 (m, 1H), 3.18 (m, 1H), 2.45 (m,1H), 2.02 (s, 3H), 1.96 (s, 3H), 1.82 (m, 1H), 1.49 (s, 9H), 1.20-1.42(m, 7H), 0.85 (m, 6H).

MS (M+H)⁺=384.

10D.(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-acetamido-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2S,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-acetamido-pyrrolidine-5-carboxylicacid t-butyl ester (11.0 mg, 0.029 mmole) in place of(+)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 11.0 mg, 100%).

¹H NMR (d₆-DMSO) δ 8.15 (d, J=14 Hz, 1H), 8.05 (d, J=14 Hz, 1H), 4.35(m, 1H), 4.28 (m, 1H), 4.19 (m, 1H), 3.59 (m, 1H), 1.90 (s, 3H), 1.81(s, 3H), 1.15-1.40 (m, 7H), 0.80 (m, 6H).

MS: (M−H)⁻=326, (M+35)⁺=362; (M+H)⁺=328, (M+23)⁺=350.

EXAMPLE 11(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonylamino-pyrrolidine-5-carboxylicAcid Hydrochloride

11A.(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5-carboxylicacid t-butyl ester is reacted with methyl chloroformate andtriethylamine in dichloromethane. The reaction is partitioned betweendichloromethane and water. The organic layer is concentrated to providethe title compound.

11B.(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 1J, substituting(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonylaminopyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

11C.(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-methoxycarbonylamino-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound is prepared according to the method described inExample 1K, substituting(±)-(2S,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonylaminopyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 12(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-4-yl)-5-carboxylicAcid Dihydrochloride

12A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-diazoacetyl-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester (405.3 mg, 0.88 mmol) and N-methylmorpholine (106 μl,0.96 mmol) in THF (20 ml) was reacted with isobutyl chloroformate (96μl, 0.93 mmole) at −10° C. for 30 minutes. To the reaction flask wascannulated a distilled diazomethane solution in ether prepared from thereaction of diazald (2.4 g) in ether (60 ml) with a solution ofpotassium hydroxide (2.4 g) in ethanol (15 ml) and water (15 ml). Thereaction was stirred for 3 hours at room temperature then diluted withether. The organic layer was washed with brine, dried (Na₂SO₄) andconcentrated to give the title compound as a thick oil (430.4 mg).

12B.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-Acetamido-3-ethyl)pentyl-3-bromoacetyl-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-diazoacetyl-5-carboxylicacid t-butyl ester (427.4 mg, 0.88 mmol) in dioxane (50 ml) was reactedwith hydrobromic acid (0.25 ml, 2.2 mmol) at 0° C. for 0.5 hours. Thereaction was quenched with saturated aqueous sodium bicarbonate (25 ml)and concentrated in vacuo. The residual aqueous layer was extracted withdichloromethane (3×50 ml). The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel using 5%methanol in dichloromethane to provide the title compound as a whitefoamy solid (379.3 mg, 80.2%).

MS: (M+H)⁺=539.

12C.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-4-yl)-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-bromoacetyl-5-carboxylicacid t-butyl ester (60 mg, 0.112 mmol) was treated with formamidineacetate (120 mg, 1.15 mmol) in liquid ammonia and heated at 45° C. in asealed tube for 20 h. The reaction was concentrated in vacuo. Theresidue was treated with aqueous NaHCO₃ and extracted withdichloromethane (5×20 ml). The combined organic layers were washed withbrine, dried over sodium sulfate, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel using 5%methanol in dichloromethane to provide the title compound as a whitesolid (21.2 mg, 39.4%).

MS: (M+H)⁺=483.

12D.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-4-yl)-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-4-yl)-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxy-methyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 12.9 mg, 66.2%).

¹H NMR (CDCl₃): δ 0.75-0.81 (m, 6H), 1.17-1.42 (m, 7H), 1.47 (s, 9H),2.03 (s, 3H), 2.66 (m, 1H), 3.50 (m, 1H), 3.73 (m, 1H), 3.86 (m, 1H),4.06 (m, 1H), 7.04 (br s, 1H), 7.86 (br s, 1H).

MS: (M+H)⁺=393.

12E.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-4-yl)-5-carboxylicAcid Dihydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-4-yl)-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester to provide the title compound solid (yield: 12.0 mg,96.0%).

¹H NMR (DMSO-d₆): δ 0.67 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H), 1.11 (m,3H), 1.23 (m, 4H), 1.78 (s, 3H), 2.33 (m, 1H), 2.70 (m, 1H), 3.69 (dt,1H), 3.95 (dd, 1H), 4.29 (m, 1H), 4.48 (dd, 1H), 7.63 (s, 1H), 8.28 (d,J=9 Hz, 1H), 9.06 (s, 1H).

MS: (M+H)⁺=337.

EXAMPLE 13(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(oxazol-2-yl)-pyrrolidine-5-carboxylicAcid Dihydrochloride

13A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N-(2-hydroxyethyl)carbamoyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 5A, substituting ethanolamine for N-methylamine hydrochloride.

13B.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(oxazolin-2-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N-(2-hydroxyethyl)carbamoyl)-pyrrolidine-5-carboxylicacid t-butyl ester, triethylamine (4 eq.), carbon tetrachloride (3.5eq.) in acetonitrile is reacted with triphenylphosphine (3.15 eq.) for16 h at room temperature. The reaction is concentrated in vacuo. Theresidue is partitioned between ethyl acetate and water. The organiclayer is washed with water, and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue is purified by chromatography onsilica gel using ethyl acetate/hexanes to provide the title compound.

13C.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(oxazol-2-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(oxazolin-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester is reacted with nickel peroxide in cyclohexaneaccording to the method described by Meyer in J. Org. Chem. 1979,497-501 to provide the title compound.

13D.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(oxazol-2-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(oxazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

13E.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(oxazol-2-yl)-pyrrolidine-5-carboxylicAcid Dihydrochloride.

The title compound is prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(oxazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 14(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(N-methylamino)-pyrrolidine-5-carboxylicAcid Dihydrochloride

14A.(±)-(2S,3R,5R)-1-Benzyl-2-vinyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester (2.08 g, 4.77 mmole) was dissolved in 50 mL ofanhydrous DMF and maintained under a nitrogen atmosphere. The solutionwas treated with sodium hydride (0.32 g, 8 mmole), and stirred at roomtemperature for 30 minutes. The solution was treated with iodomethane(0.8 ml, 12.85 mmole) and stirred for an additional 1 hour. The reactionwas quenched with water and extracted with ethyl acetate. The combinedorganic layers were concentrated to provide the crude product which waspurified by chromatography on silica gel to provide the title compoundas an oil (yield: 1.75 g, 81%).

¹H NMR (CDCl₃) δ 7.36-7.20 (m, 10H), 5.75-5.50 (br, 1H), 5.25-5.07 (m,4H), 4.75-4.50 (br, 1H), 3.97 (d, J=13.5 Hz, 1H), 3.75 (m, 1H), 3.61 (d,J=13.5 Hz, 1H), 3.50 (m, 1H), 2.93 (s, 3H), 2.45 (m, 1H), 1.75 (m, 1H),1.46 (s, 9H).

MS (M+H)⁺=451.

14B.(±)-(2R,3R,5R)-1-Benzyl-2-formyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 9C, substituting(±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester. (Yield: 747 mg, 42%.)

MS (M+H)⁺=453.

14C.(±)-(2R,3R,5R)-1-Benzyl-2-(1-oxo-3-methyl)butyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

Isobutyl magnesium chloride (2.0 M in ether, 0.68 ml) was added dropwiseover about 12 minutes to a solution of(±)-(2R,3R,5R)-1-benzyl-2-formyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicacid t-butyl ester (196 mg, 0.43 mmole) in 5 mL of anhydrous THF,maintained at −78° C. The resulting yellow solution was stirred at −78°C. for 1 hour. The solution was quenched with saturated aqueous ammoniumchloride, and extracted with ethyl acetate. The organic layer wasconcentrated and the crude product was oxidized according to theprocedure described in Example 9D. Purification by column chromatographyon silica gel, with 10-25% ethyl acetate/hexanes, provided the titlecompound (yield: 78 mg, 36%).

¹H NMR (CDCl₃) δ 7.46-7.25 (m, 10H), 5.09 (br, 2H), 4.904.60 (m, 1H),3.97-3.65 (m, 4H), 3.00 (s, 3H), 2.60 (br, 1H), 2.20-1.80 (m, 3H), 1.46(s, 9H), 0.80-0.67 (m, 7H).

MS (M+H)⁺=509.

14D. (±)-(2S,3R,5R,1′R)- and(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-amino-3-methyl)butyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 9F, substituting(±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-methyl)butyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R)-1-benzyl-2-formyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester. (Yield: 97 mg, 65%.)

MS (M+H)⁺=510.

14E. (±)-(2S,3R,5R,1′R)- and(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of (±)-(2S,3R,5R,1′R)- and(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-amino-3-methyl)butyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicacid t-butyl ester (47 mg, 0.094 mmole) was reacted with aceticanhydride (0.15 mL) in 4 mL of dichloromethane at room temperature for 2hours. The reaction was concentrated in vacuo to provide the titlecompound.

MS (M+H)⁺=552.

14F.(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(N-methylamino)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of (±)-(2S,3R,5R,1′R)- and(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-methyl)butyl-3-(N-methyl-N-benzyloxycarbonylamino)-pyrrolidine-5-carboxylicacid t-butyl ester (0.094 mmole), palladium (40 mg, 10% on carbon) andammonium formate (160 mg) in 3 mL of ethanol was heated at reflux for 30minutes. Additional palladium on carbon (15 mg) and ammonium formate (50mg) were added. The solution was stirred for an additional 15 minutesand the mixture was then filtered to remove the solids and catalyst. Thefiltrate was evaporated and the residue purified by chromatography onsilica gel 5% methanol/dichloromethane and 1% NH₄OH to provide(±)-(2S,3R,5R,1′S) (15.4 mg, lower Rf) and (±)-(2S,3R,5R,1′R) (5.4 mg,higherRf)-2-(1-acetamido-3-methyl)butyl-3-(N-methylamino)-pyrrolidine-5-carboxylicacid t-butyl esters (yield: 20.8 mg, 68%).

14G.(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(N-methylamino)-pyrrolidine-5-carboxylicAcid Dihydrochloride.

A solution of(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(N-methylamino)-pyrrolidine-5-carboxylicacid t-butyl ester (9.4 mg) was stirred with 4 N aqueous HCl (˜1.5 mL)for 2 hours. The reaction was concentrated in vacuo to provide the titlecompound (yield: 10 mg, 100%).

1H NMR (major peaks) (DMSO-d₆) δ 2.57 (s, 3H), 1.90 (s, 3H), 1.47 (m,3H), 0.91 (d, J=7.5 Hz, 3H), 0.83 (d, J=7.5 Hz, 3H).

MS:(M+H)⁺=272

EXAMPLE 15(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicAcid Dihydrochloride.

15A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

Ammonia gas was bubbled slowly through a solution of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (20 mg, 0.045 mmole) and glyoxal (6.2 uL, 0.054mmole, 1.2 equiv.) in 5 mL of methanol, maintained at 0° C., for 5minutes. After 7 hours at 0° C., additional glyoxal (10 uL) was addedand ammonia was bubbled through the solution for 5 minutes. The reactionwas allowed to stir at room temperature for 16 hours. A final additionof glyoxal (10 uL) and ammonia as, described above, followed by reactionat room temperature for an additional 4 hours effected a completereaction. The reaction was concentrated in vacuo and purified bychromatography on silica gel using 50% ethyl acetate/hexanes, followedby 10% methanol/chloroform to provide the title compound as a solid(yield: 19.9 mg, 91%).

¹H NMR (CDCl₃): d 0.67 (t, J=7.2 Hz, 3H), 0.73 (t, J=7.2 Hz, 3H),1.09-1.32 (m, 7H), 1.41 (s, 9H), 2.00 (m, 1H), 2.09 (s, 3H), 2.79 (m,1H), 3.29 (m, 1H), 3.66 (dd, J=9.6, 2.7 Hz, 1H), 3.77 (m, 1H), 3.92 (d,J=13.4 Hz, 1H), 4.04 (d, J=13.4 Hz, 1H), 4.22 (dd, 1H), 4.49 (m, 1H),6.08 (brs, 1H), 7.00 (s, 2H), 7.21-7.34 (m, 5H).

MS (M+H)⁺=483.

15B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

A mixture of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (17 mg, 0.035 mmole), ammonium formate (250 mg) and10% palladium on carbon (20 mg), in 5 mL of ethanol, was heated atreflux for 15 minutes The reaction was concentrated in vacuo and theresidue was purified by chromatography on silica gel using 5%methanol/dichlormethane and 0.25% ammonium hydroxide to provide thetitle compound as a white solid (yield: 11.3 mg, 81.9%).

MS (M+H)⁺=393.

15C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-CarboxylicAcid Dihydrochloride.

(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (11 mg, 0.028 mmole) was dissolved in 2 mL of 6N HCland stirred at room temperature for 2 hours. The reaction wasconcentrated in vacuo to provide the title compound, as an off whitesolid (yield: 11.3 mg, 100%).

¹H NMR (DMSO-d6): d 0.71 (t, J=7 Hz, 3H), 0.75 (t, J=7 Hz, 3H),1.09-1.28 (m, 7H), 1.74 (s, 3H), 2.43 (m, 1H), 2.80 (m, 1H), 3.85 (m,1H), 4.04 (m, 1H), 4.29 (m, 1H), 4.52 (m, 1H), 7.64 (s, 2H), 8.07 (br d,J=9 Hz, 1H).

MS (M+H)⁺=337 and (M−H)⁻=335.

EXAMPLE 16(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N,N-dimethylcarbamoyl)-pyrrolidine-5-carboxylicAcid Hydrochloride.

16A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N,N-dimethylcarbamoyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 5A substituting N,N-dimethylamine in place of N-methylamine(yield: 10 mg, 23%).

Mass spectrum: (M+H)⁺=488.

16B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-methylcarbamoyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(N,N-dimethylcarbamoyl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester to provide the title compound (yield: 5.5 mg, 67%).

Mass spectrum: (M+H)⁺=398.

16C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N,N-dimethylcarbamoyl)-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(N,N-dimethylcarbamoyl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (major peaks) (D₂O) d 3.15 (s, 3H), 2.94 (s, 3H), 1.98 (s, 3H),0.80 (m, 6H).

MS (M+H)⁺=342, (M−H)⁻=340.

EXAMPLE 17(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-Ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid Hydrochloride

17A. (±)-(2S,3R,5R)-1-Benzyl-2-vinyl-3-cyano-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2S,3S,5R)-1-benzyl-2-vinyl-3-formyl-pyrrolidine-5-carboxylic acidt-butyl ester (8:1 ratio) (5 g, 15.9 mmole) with hydroxylaminehydrochloride (1.28 g, 18.5 mmole) and 10% aqueous potassium carbonate(8 mL) in 20 mL of methanol, according to the procedure described byChelucci et al., Tetrahedron: Asymmetry 5:1973 (1994) provided an theintermediate oxime product.

The crude oxime, prepared above, was reacted with1,1′-carbonyldiimidazole (3.9, 23.9 mmole) in 50 mL of dichloromethanefor 3 hours, at room temperature. The reaction was concentrated in vacuoand chromatographed on silica gel with 2-10% ethyl acetate/hexanes toprovide the title compound (yield: 2.5 g, 50%).

MS (M+H)⁺=313.

17B. (±)-(2R,3R,5R)-1-Benzyl-2-formyl-3-cyano-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 1D, substituting(±)-(2S,3R,SR)-1-benzyl-2-vinyl-3-cyano-pyrrolidine-5-carboxylic acidt-butyl ester in place of(±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2.2 g, 80%).

MS (M+H)⁺=315.

17C.(±)-(2R,3R,5R)-1-Benzyl-2-(1-oxo-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1E, substituting(±)-(2S,3R,5R)-1-benzyl-2-formyl-3-cyano-pyrrolidine-5-carboxylic acidt-butyl ester in place of(±)-(2R,3R,5R)-1-benzyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield 0.4 g, 27%).

MS (M+H)⁺=399.

17D.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-amino-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1F, substituting(±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield 0.215 g, 50%).

MS (M+H)⁺=400.

17E.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 1G, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicacid t-butyl ester in place of (±)-(2R,3R,5R,1′R)- and(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield 0.210 g, 90%).

¹H NMR (CDCl₃) δ 7.25 (m, 5H), 5.08 (m, 1H), 4.40 (m, 1H), 4.15 (m, 1H),3.78 (m, 1H), 3.48 (m, 1H), 2.93 (m, 1H), 2.32 (m, 1H), 2.12 (m; 1H),2.02 (s, 3H), 1.52 (s, 9H), 1.35 (m, 7H), 0.85 (m, 6H).

MS: (M+H)⁺=442.

17F.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-cyanopyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (CDCl₃) δ 5.35 (bs, 1H), 4.00 (m, 1H), 3.83 (m, 1H), 3.39 (m,1H), 3.08 (m, 1H), 2.63 (m, 1H), 2.15 (m, 1H), 2.05 (s, 3H), 1.48 (s,9H), 1.20-1.45 (m, 7H), 0.85 (m, 6H).

MS: (M+H)⁺=352.

17G.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (d₆-DMSO) δ 9.12 (bs, 1H), 8.05 (m, 1H), 4.38 (m, 1H), 4.23 (m,1H), 3.88 (m, 1H), 3.68 (m, 1H), 3.00 (m, 1H), 2.55 (m, 1H), 2.05 (m,1H), 1.88 (s, 3H), 1.10-1.40 (m, 7H), 0.80 (m, 6H).

MS: (M+H)⁺=296, (M−H)⁻=294.

EXAMPLE 18(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-ethyl-pyrrolidine-5-carboxylicAcid Hydrochloride

18A.(±)-(2R,3S,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

To an ice-cold suspension of methyl triphenylphosphonium bromide (240mg, 0.67 mmol) in 5 mL THF was added potassium t-butoxide (60 mg, 0.54mmol) under nitrogen. The color changed immediately to bright yellow.After stirring at room temperature for 1 h,(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (100 mg, 0.225 mmol) in 5 mL THF was added andstirred at room temperature overnight. Reaction was then quenched withsaturated ammonium chloride and extracted with ethyl acetate to give thecrude product which was purified by chromatography on silica gel using30% ethyl acetate/hexanes to provide the title compound, as an oil(yield: 55 mg, 55%).

¹H NMR (CDCl₃): δ 7.45-7.20 (m, 5H), 5.94 (ddd, 1H), 5.24 (d, J=12 Hz,1H), 4.98 (d, J=18 Hz, 1H), 4.93 (d, J=10.5 HZ, 1H), 4.37 (m, 1H), 4.06(d, J=13.5 Hz, 1H), 3.80 (d, J=13.5 Hz, 1H), 3.41 (dd, J=9 Hz, J=3 Hz,1H), 3.31 (q, J=13.5 Hz, 1H), 2.60 (m, 1H), 2.26 (m, 1H), 2.00 (s, 3H),1.45 (s, 9H), 1.40-1.25 (m, 7H), 0.82 (m, 6H).

MS: (M+H)⁺=443.

18B.(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-ethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3S,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (CDCl₃): δ 5.71 (br, 1H), 4.00 (br, 1H), 3.68 (t, J=8 Hz, 1H),3.10 (m, 1H), 2.38 (m, 1H), 1.98 (s, 3H), 1.87 (m, 1H), 1.47 (s, 9H),1.55-1.20 (m, 10H), 0.93 (t, J=7.5 Hz, 3H), 0.83 (m, 6H).

MS: (M+H)⁺=355.

18C.(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-ethylpentyl-3-ethyl-pyrrolidine-5-carboxylicAcid Hydrochloride

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-ethyl-pyrrolidine-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (D₂O): δ 4.30 (br, 1H), 4.25 (t, J=7.5 Hz, 2H), 3.58 (br, 1H),2.61 (m, 1H), 2.23 (br, 1H), 2.05 (s, 3H), 1.90 (m, 1H), 1.70-1.20 (m,9H), 0.92 (t, J=7.5 Hz, 3H), 0.81 (m, 6H).

MS: (M+H)⁺=299.

EXAMPLE 19(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-propyl-pyrrolidine-5-carboxylicAcid Hydrochloride

19A.(±)-(2R,3S,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester and(±)-(2R,3S,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(trans-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according the method described inExample 18A substituting ethyl triphenylphosphonium bromide for methyltriphenylphosphonium bromide.

¹H NMR (CDCl₃) δ 7.24 (m, 5H), 5.59 (m, 1H), 5.36 (dd, J=11, 7 Hz, 1H),5.28 (bs, 1H), 4.32 (m, 1H), 4.06 (d, J=12.9 Hz, 1H), 3.80 (d, J=12.9Hz, 1H), 3.42 (dd, J=8.5, 2.0 Hz, 1H), 3.30 (dd, J=6.1, 3.1 Hz, 1H),2.88 (m, 1H), 2.29 (m, 2H), 2.01 (s, 3H), 1.64 (dd, J=6.8, 1.7 Hz, 3H),1.44 (s, 9H), 1.30 (m, 7H), 0.81 (m, 6H).

MS: (M+H)⁺=457, (M+Na)⁺=479, (M−H)−=455.

19B.(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-propyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3S,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester and(±)-(2R,3S,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(trans-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.5 mg, 54%).

MS: (M+H)⁺=369, (M+Na)⁺=391, (M−H)⁻=367.

19C.(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-propyl-pyrrolidine-5-carboxylicAcid Hydrochloride

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-ethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.5 mg, 100%).

¹H NMR (DMSO-d6) δ 8.10 (d, J=8.3 Hz, 1H), 4.24 (m, 1H), 4.17 (m, 1H),2.43 (m, 1H), 2.19 (m, 1H), 1.89 (s, 3H), 1.70 (m, 1H), 1.50-1.20 (m,12H), 0.87 (t, J=6.8 Hz, 3H), 0.84 (t, J=7.0 Hz, 3H), 0.79 (t, J=7.3 Hz,3H).

MS: (M+H)⁺=313, (M+Na)⁺=335, (M−H)⁻=311.

EXAMPLE 20(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride

20A.(±)-(2R,3R,5R,1′RS)-1-Benzyl-2-(1,2-dihydroxy)ethyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

Osmium tetroxide was added to a room temperature solution of(±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (3.5 g, 8.12 mmol) in 60 mL of 8:1 acetone/water andN-methylmorpholine N-oxide (3.0 g, 25.6 mmol). The reaction mixture wasstirred at room temperature for 6 hours and quenched with saturatedaqueous Na₂S₂O₃. The mixture was stirred for an additional 10 minutesand the solvent removed. The brownish residue was partitioned betweendichloromethane and water. The organic layer was dried over MgSO₄ andconcentrated in vacuo to provide the intermediate diol as an oil (˜3.8 g) which was used without additional purification.

MS: (M+H)⁺=466.

20B.(±)-(2R,3R,5R,1′RS)-2-(1,2-Dihydroxy)ethyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′RS)-1-benzyl-2-(1,2-dihydroxy)ethyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (21.5 g, 46.2 mmol) in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

MS: (M+H)⁺=367.

20C.(±)-(2R,3R,5R,1′RS)-1-t-Butoxycarbonyl-2-(1,2-dihydroxy)-ethyl-3-t-butyl(dimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′RS)-2-(1,2-Dihydroxy)ethyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (crude from previous step) was dissolved in 160 mL of3:1 methanol/water and di-tert-butyl-dicarbonate (14.0 g, 64 mmol) wasadded. The mixture was stirred at room temperature for 72 h. Thensolvent was removed and the residue was purified by chromatography onsilica gel using 50% ethyl acetate/hexanes to provide the title compoundas light yellow solid (yield: 15.4 g, 70%).

¹H NMR (CDCl₃): δ 0.03 (s, 3H), 0.05 (s, 3H), 1.37 (s, 9H), 0.42 (s,9H), 1.47 (s, 9H), 1.93 (d, 1H), 2.30-2.50 (m, 2H), 3.28 (d, 1H),3.66-3.43 (m, 4H), 3.85 (dd, 1H), 4.024.52 (m, 1H).

MS: (M+H)⁺=476.

20D.(±)-(2R,3R,5R)-1-t-Butoxycarbonyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R,1′RS)-1-t-butoxycarbonyl-2-(1,2-dihydroxy)ethyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (6.0 g, 12.6 mmol) was dissolved in 6:1tetrahydrofuran (THF)/water (110 mL) and treated with sodium periodate(4.4 g, 20.6 mmol). The mixture was stirred at room temperature for 3hour and diluted with ethyl acetate, washed with water, dried overMgSO₄, filtered, and concentrated in vacuo. The residue was purified bychromatography on silica gel using 20% ethyl acetate/hexanes to providethe title compound as a white waxy solid (yield: 4.4 g, 78.6%).

¹H NMR (CDCl₃) (mixture of two rotamers): δ 0.05 and 0.06 (two s, 6H),0.88 and 0.90 (two s, 9H), 1.42 and 1.44 (two s, 9H), 1.47 and 1.48 (twos, 9H), 1.89-1.99 (m, 1H), 2.37-2.43 (m, 2H), 3.54-3.67 (m, 2H),4.02-4.34 (m, 2H), 9.43 and 9.53 (two d, 1H).

MS: (M+H)⁺=444.

20E.(±)-(2R,3R,5R,1′RS)-1-t-Butoxycarbonyl-2-(1-hydroxy-3-methyl)butyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of(±)-(2R,3R,5R)-1-t-butoxycarbonyl-2-formyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (7.1 g, 16.03 mmol) in diethyl ether (75 mL) wasreacted with isobutyl magnesium chloride (24 mL, 2.0 M in ether, 48mmol) at 0° C. for 2.5 hours. The reaction was quenched with saturatedammonium chloride and diluted with ethyl acetate. The organic layer waswashed with water, and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was used in next step without furtherpurification.

MS: (M+H)⁺=502.

20F. (±)-(2R,3R,5SR)1-t-Butoxycarbonyl-2-(1-oxo-3-methyl)butyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

A solution of oxalyl chloride (16 mL, 2M in CH₂Cl₂) in 100 mL ofanhydrous dichloromethane was prepared and maintained under a nitrogenatmosphere, at −78° C. DMSO (4.26 mL, 64.1 mmol) was added slowly to thesolution. The mixture was stirred for 15 minutes and reacted with(±)-(2R,3R,5R,1′RS)-1-t-butoxycarbonyl-2-(1-hydroxy-3-methyl)butyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl in 30 mL of anhydrous dichloromethane. The solution wasstirred for 1 hour and triethylamine (17 mL, 128 mmol) was added slowlyto the reaction mixture. The solution was allowed to warm slowly to roomtemperature, quenched with saturated sodium bicarbonate and diluted withdichloromethane. The organic layer was washed with water and brine,dried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel using 5-10% ethylacetate/hexanes to provide the title compound (yield: 6.3 g, 78.8%).

¹H NMR (CDCl₃): δ 0.07 (m, 6H), 0.81-0.96 (m, 15H), 1.40 and 1.42 (twos, 9H), 1.46 and 1.47 (two s, 9H), 1.72-1.82 (m, 1H), 2.15-2.45 (m, 4H),3.47-3.69 (m, 1H), 4.28-4.46 (m, 2H).

MS: (M+H)⁺=500.

20G.(±)-(2R,3R,5R,1′RS)-1-t-Butoxycarbonyl-2-(1-amino-3-methyl)butyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample IF, substituting (±)-(2R,3R,5R)1-t-butoxycarbonyl-2-(1-oxo-3-methyl)butyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.54 g, 34.1%).

MS: (M+H)⁺=501.

20H.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1G, substituting(±)-(2R,3R,5R,1′RS)-1-t-butoxycarbonyl-2-(1-amino-3-methyl)butyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of (±)-(2R,3R,5R,1′R)- and(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 462 mg, 79.0%).

(±)-(2R,3R,5R,1′S) ¹H NMR (CDCl₃): δ 0.03 and 0.04 (two s, 6H), 0.86 (s,9H), 0.89 and 0.95 (two d, 6H), 1.04 (m, 1H), 1.17-1.25 (m, 2H), 1.44(s, 9H), 1.46 (s, 9H), 1.86 (m, 1H), 1.99 (s, 3H), 2.07 (m, 1H), 2.30(m, 1H), 3.48 (m, 1H), 3.61 (m, 1H), 3.67 (m, 1H), 4.16 (m, 1H), 4.27(m, 1H), 7.35 (brd, 1H).

MS: (M+H)⁺=543.

20I.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1H, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester in place(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)butyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

MS: (M+H)⁺=429.

20J.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 2A, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 1.5 g, 91%).

¹H NMR (CDCl₃): δ 0.92 and 0.94 (two d, 6H), 1.07 (m, 1H), 1.23-1.33 (m,2H), 1.43 (s, 9H), 1.44 (s, 9H), 1.64 (m, 1H), 2.03 (s, 3H), 2.39 (m,1H), 2.46 (m, 1H), 3.18 (m, 1H), 4.19 (m, 1H), 4.32 (m, 1H), 4.39 (m,1H), 7.12 (br d, 1H).

MS: (M+H)⁺=427.

20K.(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

To a suspension of methyl triphenylphosphonium bromide (125.6 mg, 0.35mmol) in 3 ml of anhydrous toluene was added potassium t-butoxide (1.0 Min THF. 0.31 mmol) dropwise at room temperature. After stirring for 16hours,(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamide-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (30 mg, 0.070 mmol) in 3 ml of toluene was addeddropwise and stirred for 0.5 hour. The reaction was quenched withsaturated ammonium chloride and diluted with methylene chloride. Theorganic layer was washed with water and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel using ethyl acetate to provide the titlecompound, as an white foamy solid (yield: 23.7 mg, 79.4%).

¹H NMR (CDCl₃): δ 0.92 (m, 6H), 1.26 (m, 2H), 1.44 (s, 9H), 1.47 (s,9H), 1.65 (m, 1H), 1.97 (s, 3H), 2.43 (m, 2H), 3.56 (m, 1H), 4.15 (m,2H), 4.32 (m, 1H), 5.11 (m, 1H), 5.15 (m, 1H), 5.75 (m, 1H), 7.35 (br,1H).

MS: (M+H)⁺=425.

20L.(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 16.0 mg, 99.1%).

¹H NMR (DMSO-d₆): δ 0.82 (d, 3H), 0.88 (d, 3H), 1.29 (m, 1H), 1.42 (m,1H), 1.57 (m, 1H), 1.87 (s, 3H), 1.91 (m, 1H), 2.40 (m, 1H), 2.90 (m,1H), 4.20 (m, 1H), 4.32 (m, 1H), 5.08 (dd, 1H), 5.17 (dd, 1H), 5.72(ddd, 1H), 8.09 (d, 1H), 9.16 (br s, 1H), 9.28 (br s, 1H).

MS: (M+H)⁺=269.

EXAMPLE 21(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcid Hydrochloride

21A.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

MS: (M+H)⁺=471.

21B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 8.15 (d, J=9 Hz, 1H), 4.28-4.15 (m, 2H), 3.95-3.45(m, 4H), 2.35 (m, 1H), 1.98 (m, 1H), 1.89 (s, 3H), 1.50-1.45 (m, 7H),0.81 (t, J=7.4 Hz, 3H), 0.77 (t, J=7.5 Hz, 3H).

MS: (M+H)⁺=301, (M−H)⁻=299.

EXAMPLE 22(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(pyrrol-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride

22A.(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-Acetamido-3-ethyl)pentyl-3-(2-trimethylsilylethoxycarbonylamino)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester (80 mg, 0.18 mmol) prepared according to theprocedure of Example 28 was reacted with diphenylphosphoryl azide (0.047mL, 0.216 mmol), 2-trimethylsilylethanol (0.034 mL, 0.234 mmol), andtriethylamine (0.030 mL, 0.216 mmol) in toluene (2 mL) at 75° C. for 15hours. The reaction was concentrated in vacuo and the resulting residuepurified by chromatography on silica gel using 25% ethyl acetate/hexanesto provide the title compound, as a light yellow oil (yield: 46 mg,45%).

MS: (M+H)⁺=576, (M+Na)⁺=598, (M−H)⁻=574.

22B.(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 1H, substituting(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(2-dimethylsilylethoxycarbonylamino)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(t-butyldimethylsilyloxmethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

MS: (M+H)⁺=432, (M−H)⁻=430.

22C.(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-Acetamido-3-ethyl)pentyl-3-(pyrrol-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-amino-pyrrolidine-5-carboxylicacid t-butyl ester (34 mg, 0.078 mmol) was reacted with 40% succinicdialdehyde in water (50 mg, 0.234 mmol), acetic acid (0.00044 mL, 0.0078mmol), and 4A molecular sieves (200 mg) in toluene (2 mL) at RT for 3hours. The reaction was concentrated in vacuo and the resulting residuepurified by chromatography on silica gel using 50% ethyl acetate/hexanesto provide the title compound, as an oil (yield: 7.1 mg, 19%).

MS: (M+H)⁺=482, (M+Na)⁺=504, (M−H)⁻=480.

22D.(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(pyrrol-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl ester.

The title compound is prepared according to the method described inExample 1J, substituting(±)-(2S,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(pyrrol-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.5 mg, 61%).

MS: (M+H)⁺=392, (M−H)⁻=390.

22E.(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(pyrrol-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2S,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(pyrrol-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.5 mg, 100%).

¹H NMR (D₂O) δ 7.48 (bs, 1H), 6.77 (bs, 2H), 5.97 (bs, 2H), 4.33 (m,1H), 3.70 (m, 1H), 3.07 (m, 1H), 2.43 (m, 1H), 1.92 (m, 1H), 1.75 (s,3H), 1.55 (m, 1H), 1.35-1.10 (m, 7H), 0.81 (m, 3H), 0.75 (m, 3H).

MS: (M+H)⁺=336, (M−H)⁻=334.

EXAMPLE 23(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(1-cis-N-hydroxyimino)ethyl-pyrrolidine-5-carboxylicAcid Hydrochloride

23A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(1-cis-N-hydroxyimino)ethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-acetyl-pyrrolidine-5-carboxylicacid t-butyl ester (45 mg, 0.1 mmol) prepared according to the method ofExample 8B in methanol/methylene chloride (3/1) was reacted with asolution of hydroxylamine hydrochloride (21 mg, 0.3 mmol) and sodiumhydroxide (12 mg, 0.3 mmol) in methanol (2 mL) for 2 h. The reaction wasdiluted with ethyl acetate. The organic layer was washed with water, andbrine, dried over MgSO₄, filtered and concentrated in vacuo. The residuewas purified by chromatography on silica gel using 40% ethylacetate/hexanes to provide the cis-oxime title compound (lower Rf spoton TLC), as an oil (yield: 35 mg, 75%), as well as the trans-oxime titlecompound (higher Rf spot on TLC), as an oil (yield: 13 mg, 25%).

MS: (M+H)⁺=474.

23B.(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(1-cis-N-hydroxyimino)ethylpyrrolidine-5-carboxylic Acid t-Butyl Ester.

The title compound is prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(1-cis-N-hydroxyimino)ethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (CDCl₃): δ 3.92 (br, 1H), 3.70 (m, 2H), 2.82 (m, 1H), 2.38 (m,1H), 1.88 (s, 3H), 1.78 (s, 3H), 1.39 (s, 9H), 1.401.20 (m, 7H), 0.76(m, 6H).

MS: (M+H)⁺=384.

23C.(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(1-cis-N-hydroxyimino)ethyl-pyrrolidine-5-carboxylicAcid Hydrochloride

The title compound is prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(1-cis-N-hydroxyimino)ethyl-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (D₂O): δ 4.35 (m, 1H), 4.00 (m, 1H), 3.80 (m, 1H), 3.71 (m, 1H),3.63 (m, 1H), 3.13 (q, J=8.4 Hz, 1H), 2.64 (m, 1H), 2.18 (m, 1H), 1.97(s, 3H), 1.85 (s, 3H), 1.50-1.10 (m, 7H), 0.77 (m, 6H).

MS: (M+H)⁺=328.

EXAMPLE 24(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-hydroxyimino)methyl-pyrrolidine-5-carboxylicAcid Hydrochloride

24A.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-hydroxyimino)methyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (18 mg, 0.051 mmol) prepared according to the methodof Example 2A was reacted with hydroxylamine hydrochloride (7 mg, 0.11mmol) in 1 N NaOH in methanol (3 mL) at 25° C. for 1.5 hours. Thereaction was quenched with aqueous ammonium chloride (3 ml) and water (3ml) and taken by dichloromethane (2×10 ml). The organic layer was washedwith water,and brine, dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by chromatography on silica gel using 5%methanol in dichloromethane to provide the title compound, as an oil(yield: 6 mg, 32%).

MS: (M+H)⁺=370.

24B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(N-hydroxyimino)methyl-pyrrolidine-5-carboxylicAcid Hydrochloride

The title compound is prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(N-hydroxyimino)methyl-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 25(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(methoxyimino)methyl-pyrrolidine-5-carboxylicAcid

25A. (±)-(2R,3R,5R,1′S)1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(methoxyimino)methyl-pyrrolidine-5-carboxylicAcid

(±)-(2R,3R,5R,1′S)1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-cyano-pyrrolidine-5-carboxylicacid t-butyl ester (20 mg, 0.045 mmol) prepared according to the methodof Example 17E was reacted with hydrogen chloride (0.45 mmol) in ether(2 mL) and methanol (0.1 mL) at 0° C. for 5 hours. The reaction wasneutralized with aqueous ammonium hydroxide and purified on silica gelwith 3% methanol in dichloromethane to provide the title compound, as awhite solid (yield: 5 mg, 26%).

MS: (M+H)⁺=418.

25B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-ethyl)pentyl-3-(methoxyimino)methyl-pyrrolidine-5-carboxylicAcid.

The title compound is prepared according to the method described inExample 1J, substituting (±)-(2R,3R,5R,1′S)1-Benzyl-2-(1-acetamido-3-ethyl)pentyl-3-imino-methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester, in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.9 mg, 96%).

¹H NMR (DMSO-d₆) δ 7.52 (d, J=8.7 HZ, 1H), 7.15 (s, 1H), 6.77 (s, 1H),3.68 (m, 1H), 3.61 (s, 3H), 3.22 (m, 1H), 2.51 (m, 1H), 2.23 (m, 1H),1.82 (m, 1H), 1.78 (s, 3H), 1.40 (m, 1H), 1.26 (m, 3H), 1.13 (m, 3H),0.78 (t, J=6.5 HZ, 3H), 0.72 (t, J=6.5 HZ, 3H).

MS: (M+H)⁺=328.

EXAMPLE 26(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(hydroxyacetyl)-pyrrolidine-5-carboxylicAcid Hydrochloride

26A.(±)-(2R,3R,5R,1′S,1″RS)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1,2-dihydroxy)ethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 20A substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2S,3R,5R)-1-benzyl-2-vinyl-3-(t-butyldimethylsilyloxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

26B.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(hydroxyacetyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S,1″RS)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1,2-dihydroxy)ethyl-pyrrolidine-5-carboxylicacid t-butyl ester is reacted with dibutyltin oxide in methanolaccording to the procedure of Kong in J. Carbohydrate Chem. 1993, p.557. The reaction is concentrated and the residue is redissolved indichloromethane and reacted with bromine as described in the abovereference to give the title compound.

26C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(hydroxyacetyl)-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound is prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-hydroxyacetyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 27(±)-(2S,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-amino-pyrrolidine-5-carboxylicAcid Dihydrochloride

27A.(±)-(2S,3R,5R,1′RS)-1-Benzyl-2-(1-hydroxy-3-methyl)butyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 9D, substituting isobutylmagnesium bromide in place of3-pentylmagnesium bromide.

27B.(±)-(2S,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExamples 9E-H substituting(±)-(2R,3R,5R,1′RS)-1-benzyl-2-(1-hydroxy-3-methyl)butyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3R,5R,1′RS)-1-benzyl-2-(1-hydroxy-3-ethyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicacid t-butyl ester as the starting material of the sequence in Example9E.

27C.(±)-(2S,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-amino-pyrrolidine-5-carboxylicAcid Dihydrochloride

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-aminopyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (d₆-DMSO) δ 8.64 (bs, 1H), 8.32 (bs, 1H), 8.23 (bs, 1H), 8.18 (d,J=6 Hz, 1H), 4.79 (d, J=7 Hz, 1H), 4.42 (m, 1H), 4.33 (m, 1H), 4.21 (m,1H), 4.07 (m, 1H), 3.76 (m, 2H), 2.73 (m, 2H), 1.92 (m, 3H), 0.80-0.97(m, 7H).

MS (M+H)⁺=258.

EXAMPLE 28(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid Hydrochloride

28A.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-carboxyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 2B, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester.

28B.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 2C, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester.

28C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 2E, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 8.24, 8.08 (d, J=9 Hz, 1H), 4.44, 4.36 (m, 1H),4.25, 4.15 (m, 1H), 3.98, 3.88 (m, 1H), 3.65, 3.64 (s, 3H), 3.18, 3.10(m, 1H), 2.57, 2.20 (m, 2H), 1.87, 1.83 (s, 3H), 1.57 (m, 2H), 1.36 (m,1H), 0.88 (d, J=7.5 Hz, 3H), 0.82 (d, J=7.5 Hz, 3H).

MS: (M+H)⁺=301.

EXAMPLE 29(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-CarboxylicAcid Dihydrochloride

29A.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 15A, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 27.4 mg, 83%).

MS: (M+H)⁺=455.

29B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 15B, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 19.1 mg, 95.5%).

MS: (M+H)⁺=365.

29C.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-CarboxylicAcid Dihydrochloride.

The title compound was prepared according to the method described inExample 15B, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-methyl)butyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-imidazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 0.76 (d, J=6.6 Hz, 3H), 0.82 (d, J=6.6 Hz, 3H), 1.18(t, 2H), 1.44 (m, 1H), 1.71 (s, 3H), 2.43-2.47 (m, 1H), 2.80 (m, 1H),3.83 (m, 1H), 4.05 (m, 1H), 4.28 (m, 1H), 4.55 (t, 1H), 7.65 (s, 2H),8.03 (d, J=8.4 Hz, 1H).

MS: (M+H)⁺=326.

EXAMPLE 30(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylicAcid Dihydrochloride

30A.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-carboxyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 2B, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester prepared according to the method described in Example20J in place(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 129.5 mg, >100%).

MS: (M+H)⁺=443.

30B.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-diazoacetyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 12A, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-methyl)butyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 218.8 mg, 100%).

MS: (M+H)⁺=458.

30C.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-bromoacetyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 12B, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-methyl)butyl-3-diazoacetyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-diazoacetyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 107.2 mg, 45.5%).

¹H NMR (CDCl₃): δ 0.90 (d, 6H), 1.26-1.35 (m, 3H), 1.42 (s, 9H), 1.95(s, 3H), 2.25 (m, 2H), 3.11 (m, 1H), 3.54 (dd, 1H), 3.69 (m, 1H), 3.93(dd, 2H), 4.11 (d, 1H), 4.27 (m, 1H), 4.35 (d, 1H), 5.05 (brd, 1H),7.25-7.32 (m, 5H).

MS: (M+H)⁺=509.

30D.(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1-acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 12C, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-methyl)butyl-3-bromoacetylpyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-bromoacetyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 32.3 mg, 60.4%).

MS: (M+H)⁺=455.

30E.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 1J, substituting(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 23.9 mg, 96.2%).

¹H NMR (CDCl₃): δ 0.87 (d, 3H), 0.89 (d, 3H), 1.26 (m, 1H), 1.41 (m,2H), 1.46 (s, 9H), 1.59 (m, 1H), 1.93 (s, 3H), 2.62 (m, 1H), 3.30 (m,1H), 3.54 (m, 1H), 3.79 (m, 1H), 4.01 (m, 1H), 6.11 (brd, 1H), 6.89 (s,1H), 7.63 (s, 1H).

MS: (M+H)⁺=365.

30F.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylicAcid Dihydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(imidazol-4-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(methoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester to provide the title compound solid (yield: 24.4 mg,100%).

¹H NMR (DMSO-d₆): δ 0.76 (d, J=3.6 Hz, 3H), 0.88 (d, J=3.6 Hz, 3H), 1.22(m, 1H), 1.28 (m, 1H), 1.48 (m, 1H), 1.79 (s, 3H), 2.32 (dt, 1H), 2.71(dt, 1H), 3.68 (m, 1H), 3.96 (m, 1H), 4.28 (m, 1H), 4.51 (t, 1H), 7.63(s, 1H), 8.23 (d, J=5.1 Hz, 1H), 9.10 (s, 1H), 9.67 (br s, 1H), 14.51(br s, 1H).

MS: (M+H)⁺=309.

EXAMPLE 31(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5-carboxylicAcid Dihydrochloride

31A.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-bromoacetyl-pyrrolidine-5-carboxylicacid t-butyl ester (36.5 mg, 0.07 mmol) was reacted with thioformamide(21.4 mg, 0.35 mmol) in ethanol (5 ml) at reflux for 4 hours. Thereaction was concentrated in vacuo. The residue was treated with 5 ml ofaqueous NaHCO₃ and extracted with dichloromethane (4 ×5 ml). The organiclayers were washed with brine, dried over Na₂SO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using ethyl acetate to provide the title compound, as a whitesolid (yield: 23.8 mg, 70.4%).

MS: (M+H)⁺=482.

31B.(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5-carboxylicAcid Dihydrochloride.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-4-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxy′methyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 18.5 mg, 100%).

¹H NMR (DMSO-d₆): δ 0.62 (d, J=4.2 Hz, 3H), 0.72 (d, J=4.2 Hz, 3H), 1.05(m, 1H), 1.12 (m, 1H), 1.30 (m, 1H), 1.72 (s, 3H), 2.14 (dt, 1H), 2.59(dt, 1H), 3.69 (m, 1H), 3.92 (br m, 1H), 4.21 (m, 1H), 4.38 (br m, 1H),7.46 (d, J=1.2 Hz, 1H), 8.02 (d, J=5.1 Hz, 1H), 9.04 (d, J=1.2 Hz, 1H),9.39 (br s, 1H), 9.48 (br s, 1H).

MS: (M+H)⁺=326.

EXAMPLE 32(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(thiazol-2-yl)-pyrrolidine-5-carboxylicAcid Dihydrochloride

32A.(±)-(2R,3R,5R,1′S)-1-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-carbamoyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-carboxyl-pyrrolidine-5-carboxylicacid t-butyl ester (0.258 g, 0.584 mmol) was reacted with isobutylchloroformate (80 mg, 0.84 mmol) and N-methylmorpholine (59 mg, 0.584mmol) in THF (10 mL) at 0° C. for 0.25 hours. Aqueous ammonium hydroxide(0.39 mL) was added and the reaction was stirred at 0° C. for 0.5 hours.The reaction was diluted with ethyl acetate. The organic layer waswashed with water, and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 100% ethyl acetate to 5% methanol-ethyl acetate toprovide the title compound, as a glass (yield: 182 mg, 70.7%).

¹H NMR (CD₃OD) δ 4.70 (m, 1H), 4.36 (q, J=3 Hz, 1H), 4.05 (m, 1H), 2.87(q, of t, J=9 and 3 Hz, 1H), 2.52 (m, 1H), 2.36 (m, 1H), 1.94 (d, 3H),1.63 (m, 1H), 1.41-1.53 (m, 18H), 1.3 (m, 2H), 0.9-0.18 (m, 6H).

MS: (M+H)⁺=442.

32B.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-thiocarbamoyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-carbamoyl-pyrrolidine-5-carboxylicacid t-butyl ester (70 mg, 0.159 mmol) was reacted with P₂S₁₀ (8.5 mg,0.019 mmol) in 4 ml tetrahydrofuran and 1 ml of methylene chloride atroom temperature. After 1.25 hrs, 9.6 mg of P₂S₁₀ was added. Thestarting material had been consumed after 2 hrs. The mixture was dilutedwith ethyl acetate, washed with water and brine, dried over MgsO₄,filtered and concentrated. Tlc analysis showed two spots and the massspectrum indicated it was a mixture of monothio and di-thio compounds.The material was used in the next reaction without further purification.

MS: (M+H)⁺=458,474.

32C.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-2-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-thiocarbamoyl-pyrrolidine-5-carboxylicacid t-butyl ester (73 mg, 0.16 mmol) was reacted withchloroacetaldehyde (50% in water) (0.02 ml, 0.16 mmol) in 5 ml ofacetone at 75° C. Magnesium sulfate (0.9 g) and additionalchloroacetaldehyde was added at intervals over the next 5 hr when tillcomplete conversion of starting material. The reaction was diluted withethyl acetate, washed with water, and brine, dried over MgSO₄, filteredand concentrated in vacuo. The residue was purified by chromatography onsilica gel using 100% ethyl acetate to provide the title compound, as aglass (yield: 12.6 mg, 16.3%).

¹H NMR (CDCl₃) δ 7.69 (m, 1H), 7.45 (m, 1H), 4.44 (m, 1H), 4.28 (m, 2H),3.52 (m, 1H), 2.7 (m, 1H), 2.5 (m, 1H), 1.99 (s, 3H), 1.44 (s, 9H), 1.37(s, 9H), 1.27 (m, 3 H), 0.95 (m, 6 H).

MS: (M+H)⁺=482.

32D.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methylbutyl-3-(thiazol-2-yl)-pyrrolidine-5-carboxylicAcid Dihydrochloride

The title compound was prepared according to the method described inExample 1K, substituting (±)-(2R,3RSR,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(thiazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 10.1 mg, 82%).

¹H NMR (DMSO-d₆) δ 8.1 (d, J=10 Hz, 1H), 7.79 (d, J=4 Hz, 1H), 7.69 (d,J=4 Hz, 1H), 4.49 (t, J=7.5, 1H), 4.22 (m, 1H), 4.14 (t, J=9 Hz, 1H),4.01 (q, J=10 Hz, 1H), 2.80 (m, 1H), 2.25 (m, 1H), 1.78 (s, 3H), 1.47(m, 1H), 1.25 (m, 2H), 0.83 (d, J=6.2 Hz, 3H), 0.75 (d, J=6.2 Hz, 3H).

MS: (M−H)⁻=324, (2M−1)⁻=649, (M+35)⁺=360.

EXAMPLE 33(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

33A.(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester and(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(trans-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 20K substituting (chloromethyl)triphenylphosphonium chloride inplace of methyltriphenylphosphonium bromide. The higher Rf 0.73 (ethylacetate) new spot was identified to be the cis-isomer (yield: 38.4 mg,40%) and the lower Rf 0.57 (ethyl acetate) spot trans-isomer (yield: 42mg, 43%).

cis-isomer ¹H NMR (CDCl₃): δ 7.44 (br, 1H), 6.13 (d, J=7.5 Hz, 1H), 5.32(dd, J=9 Hz, J=7.5 Hz, 1H), 4.31-4.16 (m, 2H), 3.65 (m, 1H), 3.12 (m,1H), 2.50 (m, 1H), 1.98 (s, 3H), 1.62 (m, 1H), 1.47 (s, 9H), 1.45 (s,9H), 1.30-1.07 (m, 2H), 0.82 (m, 6H).

MS: (M+H)⁺=459.

trans-isomer ¹H NMR (CDCl₃): δ 6.12-5.90 (m, 2H), 4.30-4.07 (m, 2H),3.64 (m, 1H), 2.62-2.37 (m, 2H), 1.98 (s, 3H), 1.69 (m, 1H), 1.48 (s,9H), 1.45 (s, 9H), 1.26 (m, 2H), 0.91 (m, 6H).

MS: (M+H)⁺=459.

33B.(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (10 mg, 0.022 mmol) was reacted with trifluoroaceticacid (1.8 mL) in dichloromethane (0.4 mL) at room temperature for 7hours. The reaction was concentrated in vacuo. The residue was dried onhigh vacuum to provide the title compound.

¹H NMR (DMSO-d₆): δ 8.015 (d, J=7.63 Hz, 1H), 6.42 (d, J=7.02 Hz, 1H),5.89 (dd, J=7.02 Hz, J=8.7 Hz, 1H), 4.42 (m, 1H), 4.17 (m, 1H), 3.59 (m,1H), 3.31 (m, 1H), 2.47 (m, 1H), 1.88 (s, 3H), 1.84 (m, 1H), 1.58 (m,1H), 1.39 (m, 1H), 1.29 (m, 2H), 0.885 (d, J=6.71 Hz, 3H), 0.83 (d,J=6.41, 3H).

MS: (M+H)⁺=303.

EXAMPLE 34(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(trans-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

34B.(±)-(2R,3SR,1′S)-2-(1-acetamido-3-methylbutyl-3-(trans-2-chloro-vinyl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(trans-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 8.04 (d, J=7.93 Hz, 1H), 6.355 (d, J=13.1 Hz, 1H),5.93 (dd, J=13.1 Hz, J=9.32 Hz, 1H), 4.33 (m, 1H), 4.19 (m, 1H), 2.95(m, 1H), 2.40 (m, 1H), 1.94 (m, 1H), 1.88 (s, 3H), 1.58 (m, 1H), 1.39(m, 1H), 1.29 (m, 1H), 0.89 (d, J=6.7 Hz, 3H), 0.825 (d, J=6.7 Hz, 3H).

MS: (M+H)⁺=303.

EXAMPLE 35(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

35A.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

To a suspension of ethyl triphenylphosphonium bromide (479 mg, 1.29mmol) in 3 mL anhydrous toluene was added potassium t-butoxide (1.0 M inTHF, 0.94 mmol) dropwise at room temperature. After stirring for 2.5hours,(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (90 mg, 0.211 mmol) in 5 mL toluene was addeddropwise and stirred for 1 hour. The reaction was quenched withsaturated aqueous ammonium chloride and diluted with ethyl acetate. Theorganic layer was washed with water, and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel using 50% ethyl acetate/hexanes to providethe title compound, as an oil (yield: 70.6 mg, 76%).

MS: (M+H)⁺=439.

35B. (±)-(2R,3S5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vinyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 8.04 (d, J=7.5 Hz, 1H), 5.51 (m, 1H), 5.26 (m, 1H),4.32 (m, 1H), 4.18 (m, 1H), 3.45 (m, 1H), 3.18 (m, 1H), 2.39 (m, 1H),1.88 (s, 3H), 1.73 (m, 1H), 1.63 (dd, 3H), 1.58 (m, 1H), 1.38 (m, 1H),1.28 (m, 1H), 0.88 (d, J=6 Hz, 3H), 0.81 (dd, J=6 Hz, 3H).

MS: (M+H)⁺=283.

EXAMPLE 36(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-dimethyl-vin-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

36A.(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(2.2-dimethyl-vin-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 20K substituting isopropyl triphenylphosphonium iodide in placeof methyltriphenylphosphonium bromide (yield: 22.6 mg, 33%).

¹H NMR (CDCl₃): δ 7.77 (d, 1H), 5.06 (d, J=10 Hz, 1H), 4.18 (m, 2H),3.50 (m, 1H), 2.69 (m, 1H), 2.32 (m, 1H), 1.97 (s, 3H), 1.70 (s, 3H),1.64 (s, 3H), 1.65 (m, 1H), 1.47 (s, 9H), 1.44 (s, 9H), 1.30-1.00 (m,3H), 0.93 (d, J=6 Hz, 3H), 0.88 (d, J=6 Hz, 3H).

MS: (M+H)⁺=453.

36B.(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(2.2-dimethyl-vin-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(2,2-dimethyl-vin-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 8.01 (d. J=7.5 HZ, 1H), 4.99 (d, J=10 Hz, 1H), 4.30(m, 1H), 4.14 (m, 1H), 3.40 (m, 1H), 3.06 (m, 1H), 2.36 (m, 1H), 1.86(s, 3H), 1.66 (s, 3H), 1.63 (s, 3H), 1.57 (m, 1H), 1.39-1.20 (m, 3H),0.88 (d, J=6 Hz, 3H), 0.81 (d, J=6 Hz, 3H).

MS: (M+H)⁺=297.

EXAMPLE 37(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

37A.(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

n-Butyllithium (1.6M in hexanes, 0.61 mL, 0.97 mmol) was added todiisopropylamine (136 μL, 0.97 mmol) in 4 mL THF at −78° C. and stirredfor 30 min. diethyl difluoromethylphosphonate (182 mg, 0.97 mmol) wasadded, the colorless solution changed slowly to yellow after stirring at−78° C. for 2 hours.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (59 mg, 0.138 mmol) in 3 mL THF was added, stirred at78° C. for 30 min, then warm up to room temperature. The mixture wasthen heated at reflux for 1.5 hour, and stirred at room temperatureovernight. The reaction was quenched with saturated aqueous ammoniumchloride, and diluted with ethyl acetate. The organic layer was washedwith water, and brine, dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by chromatography on silica gel using50% ethyl acetate/hexanes to provide the title compound, as a lightyellow oil (23.4 mg, 37%).

¹H NMR (CDCl₃): δ 7.44 (d, 1H), 5.92 (ddd, 1H), 4.30-4.00 (m, 2H), 3.55(m, 1H), 2.69 (m, 1H), 2.45 (m, 1H), 2.00 (s, 3H), 1.47 (s, 9H), 1.43(s, 9H), 1.45-1.00 (m, 4H), 0.91 (m, 6H).

MS: (M+H)⁺=461.

37B.(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(2.2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vin-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 8.04 (d, J=7.5 Hz, 1H), 4.59 (ddd, 1H), 4.23 (m,1H), 4.14 (m, 1H), 3.48 (m, 1H), 3.39 (m, 1H), 2.91 (m, 1H), 2.43 (m,1H), 1.85 (s, 3H), 1.58 (m, 1H), 1.40 (m, 1H), 1.31 (m, 1H), 1.22 (m,1H), 0.89 (d, J=7.5 Hz, 3H), 0.83 (d, J=7.5 Hz, 3H).

MS: (M+H)⁺=305.

EXAMPLE 38(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

38A.(±)-(2R,3R,5R,1′S,1″RS)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 4A substituting 2-propynyl magnesium bromide in place of ethylmagnesium bromide and substituting(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (250 mg, 0.587 mmol) in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester the crude product was used directly in the nextreaction.

MS: (M+H)⁺=453.

38B.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester was reacted with Jones reagent (3.0 M in acetone,0.33 mL) in acetone (90 mL) at 0° C. to room temperature for 1 hour. Thereaction was diluted with ethyl acetate. The organic layer was washedwith water, and brine, dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by chromatography on silica gel using50% ethyl acetate/hexanes to provide the title compound, as a whitesolid (yield: 143 mg, 54%).

MS: (M+H)⁺=451.

38C.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-oxo-1-ethynyl)methyl-pyrrolidine-5-carboxylicacid t-butyl ester (140 mg, 0.311 mmol) was reacted with hydrazinemonohydrate (0.24 mL, 4.944 mmol) in ethanol (12 mL) at room temperaturefor 4 hours. The reaction was concentrated in vacuo. The residue waspurified by chromatography on silica gel using ethyl acetate to providethe title compound, as a white solid (yield: 131 mg, 91%).

MS: (M+H)⁺=465.

38D.(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vinyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 8.13 (d, J=7.5 Hz, 1H), 7.65 (d, J=2.2 Hz, 1H), 6.20(d, J=2.2 Hz, 1H), 4.39 (m, 1H), 4.25 (m, 1H), 3.94 (m, 1H), 3.56 (q,J=7.5 Hz, 1H), 2.62 (m, 1H), 2.17 (m, 1H), 1.87 (s, 3H), 1.42 (m, 1H),1.21 (m, 1H), 1.11 (m, 1H), 0.80 (d, J=6.6 Hz, 3H), 0.71 (d, J=6.6 Hz,3H).

MS: (M+H)⁺=309.

EXAMPLE 39(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt and(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

39A.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester and(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-oxo-1-ethynyl)methyl-pyrrolidine-5-carboxylicacid t-butyl ester (31 mg, 0.07 mmol) was reacted with hydroxyaminehydrochloride (4.9 mg, 0.07 mmol) and sodium carbonate (3.7 mg, 0.035mmol) in ethanol (3 mL) at reflux for 30 hours. The reaction wasconcentrated in vacua. The residue was purified by chromatography onsilica gel using 3% methanol/dichloromethane to provide the titlecompound, as an oil (yield: 11.5 mg, 36%).

MS: (M+H)⁺=466.

39B.(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt and(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 33B, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-3-yl)-pyrrolidine-5-carboxylicacid t-butyl ester and(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(isoxazol-5-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vinyl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 8.91, 8.54 (d, 1H), 8.12, 8.05 (d, J=7.5 Hz, 1H),6.64, 6.43 (d, 1H), 4.48, 4.51 (m, 1H), 4.28 (m, 1H), 3.97, 3.89 (m,1H), 3.70, 3.81 (m, 1H), 2.72 (m, 1H), 2.20, 2.25 (m, 1H), 1.83, 1.80(s, 3H), 1.48 (m, 1H), 1.34-1.10 (m, 2H), 0.83, 0.84 (d, J=6 Hz, 3H),0.77, 0.78 (d, J=6 Hz, 3H).

MS: (M+H)⁺=310.

EXAMPLE 40(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

40A.(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-(hydroxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (54.2 g, 0.17 mol) and 4-(dimethylamino)pyridine (0.5g, 4.1 mmol), in anhydrous pyridine (400 mL) was reacted with aceticanhydride (30 mL, 0.32 mol) at 0° C. for 1 hour then allowed to warm toroom temperature. The reaction was stirred an additional 16 hours. Thepyridine was removed in vacuo at 30° C. The residue was partitionedbetween ethyl acetate (100 mL) and of water (400 mL). The aqueous layerwas extracted with ethyl acetate (3×100 mL) and the combined ethylacetate layers were washed with brine, dried with MgSO₄, filtered, andconcentrated. The crude product was purified by chromatography on silicagel using 10% ethyl acetate/hexanes to provide the title compound as acolorless oil (yield: 49.6 g, 81%).

¹H NMR (CDCl₃) δ 7.28 (m, 4H), 7.21 (m, 1H), 5.68 (m, 1H), 5.21 (m, 2H),4.16 (dd, J=6.3, 10.7 Hz, 1H), 4.10 (dd, J=7.3, 10.7 Hz, 1H), 3.92 (d,J=13.7 Hz, 1H), 3.64 (d, J=13.7 Hz, 1H), 3.52 (m, 1H), 3.50 (m, 1H),2.33 (m, 1H), 2.26 (m, 1H), 2.02 (s, 3H), 1.62 (m, 1H), 1.45 (s, 9H).

MS (M+H)⁺=360.

40B. (±)-(2R,3R,5R,1′R)- and(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1,2-dihydroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R)-1-benzyl-2-vinyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (52.5 g, 0.15 mol) and 4-methylmorpholine N-oxide(54.7 g, 0.47 mol) in acetone (540 mL) and water (60 mL) was reactedwith osmium tetroxide (200 mg, 0.8 mmol). After 24 hours, the reactionwas quenched with 10% sodium thiosulfate (250 mL) concentrated in vacuo.The aqueous layer was extracted with ethyl acetate (3×300 mL) and thecombined organic layers were washed with brine, dried over MgSO₄,filtered and concentrated. The residue was purified by chromatography onsilica gel using a gradient elution of ethyl acetate and dichloromethaneto provide the title compound as a viscous oil (yield: 41.2 g, 72%).

¹H NMR (DMSO) δ 7.32 (m, 3H), 7.30 (m, 1H), 7.22 (m, 1H), 4.48 (t, J=5.4Hz, 1H), 4.42 (d, J=5.4 Hz, 1H), 4.04 (m, 1H), 4.01 (m, 1H), 3.97 (m,1H), 3.80 (d, J=13.2 Hz, 1H), 3.78 (m, 1H), 3.43 (m, 1H), 3.39 (m, 1H),3.32 (m, 1H), 3.07 (t, J=4.9 Hz, 1H), 2.48 (m, 1H), 2.19 (m, 1H), 1.99(s, 3H), 1.57 (dt, J=13.7, 2.0 Hz, 1H), 1.38 (s, 9H).

MS (M+H)⁺=394.

40C. (±)-(2R,3R,5R,1′R) and(±)-(2R,3R,5R,1′S)-2-(1,2-Dihydroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′R) and(±)-(2R,3R,5R,1′S)-1-Benzyl-2-(1,2-dihydroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (24 g, 61 mmol) in ethanol (300 mL) was reacted withammonium formate (38.5 g, 0.61 mol) and 10% Pd/C (2 g) for 2 hours atreflux. The reaction was cooled and the catalyst removed by filtrationthrough Celite. The filtrate was concentrated in vacuo to provide thetitle compound (yield: 16.7 g, 90%).

¹H NMR (DMSO) δ 4.56 (m, 1H), 4.30 (m, 1H), 4.06 (dd, J=5.8, 10.9 Hz,2H), 3.79 (dd, J=8.8, 10.5 Hz, 2H), 3.49 (m, 4H), 3.00 (m, 1H), 2.35 (m,1H), 2.16 (dt, J=12.6, 8.5 Hz, 1H), 2.01 (s, 3H), 1.52 (m, 1H), 1.40 (s,9H).

MS (M+H)⁺=304.

40D. (±)-(2R,3R,5R,1′R) and (±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl2-(1,2-dihydroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic Acidt-Butyl Ester.

(±)-(2R,3R,5R,1′R) and(±)-(2R,3R,5R,1′S)-2-(1,2-Dihydroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (33.4 g, 0.11 mol) in methanol (250 mL) and water (50mL) was reacted with di-t-butyl dicarbonate (33.6 g, 0.15 mol) for 48hours at room temperature. The methanol was removed in vacuo and theresidue diluted with water (500 mL), and extracted with ethyl acetate(3×200 mL). The combined ethyl acetate layers were washed with brine,dried with MgSO₄, filtered and concentrated. The residue waschromatographed on silica gel using methanol/dichloromethane to providethe title compound as a white solid (yield: 32.8 g, 78%)

¹H NMR (DMSO) δ 4.80 (m, 1H), 4.45 (m, 1H), 4.08 (m, 1H), 3.91 (m, 2H),3.82 (m, 1H), 3.71 (m, 1H), 3.28 (m, 2H), 2.48 (m, 1H), 2.07 (m, 2H),2.01 (m, 3H), 1.39 (m, 18H).

MS (M+H)⁺=404.

40E (±)-(2R,3R,5R,1′R) and (±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl2-(1-hydroxy-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′R) and (±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl2-(1,2-dihydroxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylic acidt-butyl ester (26.5 g, 66 mmol) in anhydrous dimethylformamide (200 mL)was reacted with imidazole (8.9 g, 0.13 mol) and triisopropylsilylchloride (19.0 g, 99 mmol) for 4 hours at room temperature. The solventwas removed under vacuum and the residue partitioned between 300 mL ofwater and 150 mL of ethyl acetate. The aqueous layer was extracted withethyl acetate (2×100 mL), and the combined ethyl acetate layersextracted with brine, dried with MgSO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel using 10% ethylacetate/hexanes to provide the title compound as a colorless oil (yield:28.9 g, 79%).

¹H NMR (CDCl₃) δ 4.22 (m, 1H), 4.04 (m, 3H), 3.87 (t, J=2.0 Hz, 1H),3.74 (dd, J=4.9, 9.8 Hz, 1H), 3.58 (dd, J=7.8, 10.2 Hz, 1H), 3.39 (bs,1H), 2.61 (m, 2H), 2.03 (s, 3H), 1.75 (m, 1H), 1.46 (m, 18H), 1.07 (m,18H).

MS (M+H)⁺=560.

40F(±)-(2R,3R,5R)-1-t-Butoxycarbonyl-2-(1-oxo-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

Dimethylsulfoxide (6 mL, 85 mmol) was added slowly to a solution ofoxalyl chloride (2 M) (19.3 mL, 38.6 mmol) in dry dichloromethane (70mL) at −78° C. After 10 minutes, a solution of (±)-(2R,3R,5R,1′R) and(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl2-(1-hydroxy-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (14.4 g, 26 mmol) in dry dichloromethane (75 mL) wasadded at a rate such that the temperature did not exceed −70° C. After1.5 hours, triethylamine (18 mL, 0.13 mol) was added and the temperatureallowed to rise to 0° C. The reaction was quenched with a solution ofammonium chloride, diluted with water, and extracted withdichloromethane (3×100 mL). The combined dichloromethane layers wereextracted with brine, dried with MgSO₄, filtered and concentrated. Theresidue was purified by chromatography on silica gel using 10% ethylacetate/hexanes to provide the title compound as a colorless oil:(yield: 11 g, 77%).

¹H NMR (CDCl₃) δ 4.32 (m, 6H), 2.43 (m, 2H), 2.04 (s, 3H), 1.78 (m, 1H),1.48 (s, 9H), 1.41 (s, 9H), 1.1 (m, 21H).

MS (M+H)⁺=558.

40G (±)-(2R,3R,5R,1′R) and (±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl2-(1-amino-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R)-1-t-Butoxycarbonyl2-(1-oxo-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (22 g, 39 mmol) in methanol (1 L) was reacted withammonium acetate (77 g, 1.0 mol) and sodium cyanoborohydride (24.8 g,0.39 mol) at reflux for 2 hours. The solvent was removed under in vacuo,and the residue was partitioned between water (300 mL) anddichloromethane (300 mL). The aqueous layer was extracted withdichloromethane (2×100 mL) and the combined organic layers were washedwith brine, dried with MgSO₄, filtered and concentrated to provide thetitle compound (crude yield: 22.0 g, 100%).

40H (±)-(2R,3R,5R,1′R) and(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′R) and(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-amino-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (approx 39 mmol) in dichloromethane (500 mL) wasreacted with acetic anhydride (18 mL, 0.19 mol), triethylamine (27.5 mL,0.20 mol) and dimethylaminopyridine (50 mg, 0.39 mmol) for 18 hours atroom temperature. The reaction was quenched with a solution of ammoniumchloride. The aqueous layer was extracted with dichloromethane (3×100mL) and the combined organic layers extracted with brine, dried withMgSO₄, filtered, and concentrated. The residue was chromatographed onsilica gel using ethyl acetate/hexanes to provide the title compound(±)-(2R,3R,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (9.14 g, 39%) and(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (9.75 g, 41% ) as white solids.

(±)-(2R,3R,5R,1′R) ¹H NMR (CDCl₃) δ 7.38 (d, J=8.3 Hz, 1H), 4.34 (m,1H), 4.20 (dd, J=2.4, 10.3 Hz, 1H), 4.09 (dd, J=8.8, 10.2 Hz, 1H), 4.02(dd, J=7.3, 10.1 Hz, 1H), 3.88 (m, 1H), 3.71 (dd, J=4.4, 10.3 Hz, 1H),3.65 (dd, J=7.9, 10.3 Hz, 1H), 2.74 (m, 1H), 2.60 (m, 1H), 2.04 (s, 3H),1.98 (s, 3H), 1.69 (dt, J=14.1, 2.5 Hz, 1H), 1.46 (s, 9H), 1.42 (s, 9H),1.07 (m, 21H).

MS (M+H)⁺=601.

(±)-(2R,3R,5R,1′S) ¹H NMR (CDCl₃) δ 6.82 (d, 1H), 4.10 (m, 4H), 3.81 (m,3H), 2.55 (m, 2H), 1.98 (m, 7H), 1.46 (s, 9H), 1.42 (s, 9H), 1.07 (m,21H).

MS (M+H)⁺=601.

40I (±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-(acetoxymethyl)-pyrrolidine-5-carboxylicacid t-butyl ester (8.2 g, 13.66 mmol) in methanol (200 mL) and water(50 mL) was reacted with potassium carbonate (19 g, 136 mmol) at roomtemperature for 2 hr. The solvent was then removed in vacuo and theresidue was partitioned between water (100 mL) and dichloromethane(3×100 mL). The organic extracts were dried over magnesium sulfate,filtered and concentrated in vacuo to provide the title compound as acolorless oil.

40J (±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-formyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 2A substituting (±)-(2R,3R,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-(2-triisopropylsilyloxy)ethyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 5.9 g, 78%).

¹H NMR (CDCl₃) δ 1.04-1.07 (m, 21H), 1.42 (s, 9H), 1.43 (s, 9H), 1.99(s, 3H), 2.42 (m, 1H), 2.62 (m, 1H), 3.04 (m, 1H), 3.69 (m, 1H), 3.82(m, 1H), 4.08 (m, 1H), 4.38 (m, 1H), 4.57 (t, 1H), 7.33 (br d, 1H), 9.65(s, 1H).

MS: (M+H)⁺=557.

40K (±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 35A substituting (±)-(2R,3R,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 5.9 g, 78%).

¹H NMR (CDCl₃) δ 1.03-1.10 (m, 21H), 1.44 (s, 9H), 1.47 (s, 9H), 1.55(m, 1H), 1.64 (dd, 3H), 1.96 (s, 3H), 2.55 (m, 1H), 3.42 (m, 1H),3.62-3.71 (m, 3H), 4.20 (dd, 1H), 4.30 (m, 1H), 5.39 (m, 1H), 5.48 (m,1H), 7.73 (br d, 1H).

MS: (M+H)⁺=569.

40L (±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (4.85 g, 8.54 mmol) in THF (100 mL) was reacted withtetrabutyl ammonium fluoride (1M in THF) (12.8 mL, 12.8 mmol) for 30minutes at room temperature. Water (100 mL) was added followed byextraction using dichloromethane (2×100 mL). This organic layers weredried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel using 2/1:ethyl acetate/hexane to provide the title compound as a colorless solid(yield: 3.1 g, 89%).

¹H NMR (CDCl₃): d 1.44 (s, 9H), 1.47 (s, 9H), 1.56 (dd, 3H), 1.80 (m,1H), 2.02 (s, 3H), 2.67 (m, 1H), 3.11 (t, 3H), 3.44 (dd, 1H), 3.59 (dd,1H), 3.74-3.84 (m, 2H), 4.15 (dd, 1H) 5.39 (m, 1H), 5.58 (m, 1H), 6.42(br d, 1H).

MS: (M+H)⁺=413.

40M(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 33B, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(trans-2-chloro-vinyl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 18.0 mg, 100%).

¹H NMR (DMSO-d₆): d 1.66 (dd, 3H), 1.71 (dt, 1H), 1.87 (s, 3H), 2.41(dt, 1H), 3.18 (m, 1H), 3.43 (dd, 1H), 3.61 (m, 1H), 4.13 (m, 1H), 4.35(m, 1H), 5.25 (m, 1H), 5.51 (m, 1H), 8.05 (d, 1H), 9.16 (br s, 2H).

MS: (M+H)⁺=257.

EXAMPLE 41(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

41A (±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (600 mg, 1.46 mmol) in dichloromethane (50 mL) wasreacted with Dess-Martin Periodinane (928 mg, 2.18 mmol) for 1 hour atroom temperature. The reaction was quenched with 1M aqueous sodiumthiosulfate (50 mL), stirred for 20 minutes then extracted withdichloromethane (3×100 mL). The organic layer was dried over magnesiumsulfate, concentrated in vacuo. The residue was purified by columnchromatography on silica gel using 2/1: ethyl acetate/hexane to providethe title compound (yield: 547 mg, 92%).

¹H NMR (CDCl₃) d 9.40 (d, J=1 Hz, 1H), 7.88 (bd), 5.69 (m, 1H), 5.27 (m,1H), 4.78 (dd, J=9.5, 1.0 Hz, 1H), 4.21 (t, J=8.0 Hz, 1H), 3.45 (m, 2H),2.41 (m, 1H), 2.09 (s, 3H), 1.69 (dd, J=7.0, 1.0 Hz, 3H), 1.55 (m, 1H),1.46 (s, 9H), 1.40 (s, 9H).

MS: (M+H)⁺=411, (M−H)−=409.

41B (±)-(2R,3S,5R,1′R,2′R) and(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (780 mg, 1.90 mmol) in THF (20 mL) was added dropwiseto a solution of ethylmagnesium bromide (3M in ether) (3.17 mL, 9.51mmol) in THF (15 mL) at room temperature and reacted for 40 minutes. Thereaction was quenched with water (20 mL) and saturated aqueous ammoniumchloride (20 mL) followed by extraction using dichloromethane (3×50 mL).The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 2/1: ethyl acetate/hexane to provide the titlecompounds (±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 472 mg, 56%) and(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 82 mg, 10%) as a colorless oils.

(±)-(2R,3S,5R,1′R,2′R)=MS: (M+H)⁺=441, (M+Na)+=463, (M−H)−=439.

(±)-(2R,3S,5R,1′R,2′S)=MS: (M+H)⁺=441, (M+Na)+=463, (M−H)−=439.

41C(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (300 mg, 0.68 mmol) was reacted with trifluoroaceticacid (8 mL) in dichloromethane (2 mL) at room temperature for 6 hrs. Thereaction was concentrated in vacuo overnight to provide the titlecompound (yield: 311 mg) as a colorless solid.

¹H NMR (500 MHz, DMSO-d₆) δ: 7.89 (d, J=8.7 Hz, 1H), 5.48 (m, 1H), 5.29(m, 1H), 4.30 (m, 1H), 4.02 (m, 1H), 3.73 (m, 1H), 3.43 (m, 1H), 3.15(m, 1H), 2.41 (m, 1H), 1.82 (s, 3H), 1.63 (m, 1H), 1.59 (dd, J=6.8, 1.9Hz, 3H), 1.55 (m, 1H), 1.27 (m, 1H), 0.85 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=285, (M+Na)⁺=307, (M−H)⁻=283.

EXAMPLE 42(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

42A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (460 mg, 1.05 mmol) was reacted with Dess-MartinPeriodinane (666 mg, 1.57 mmol) in dichloromethane (30 mL) at roomtemperature for 17 hours. The reaction was quenched with 1 M aqueoussodium thiosulfate (50 mL and stirred for 20 minutes. The reaction wasextracted with dichloromethane (3×100 mL). The organic layer was driedover magnesium sulfate,filtered, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel using 2:1: ethylacetate/hexane to provide the title compound as a colorless semi-solid(yield: 440 mg, 96%).

MS: (M+H)⁺=439, (M+Na)+=461, (M−H)−=437.

42B (±)-(2R,3S,5R,1′R,2′R) and(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (435 mg, 0.99 mmol) in methanol (30 mL) was reactedwith sodium borohydride (188 mg, 4.97 mmol) at room temperature for 0.5hours. The solvent was removed in vacuo and water (30 mL) was added. Theaqueous layer was extracted with dichloromethane (3×50 mL). This organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica gelusing 2:1 ethyl acetate/hexane to provide the title compounds(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 305 mg, 70%) and compounds(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 17 mg, 4%).

42C(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (300 mg, 0.68 mmol) was reacted with trifluoroaceticacid (8 mL) in dichloromethane (2 mL) at room temperature for 6 hrs. Thereaction was concentrated in vacuo overnight and triturated withacetonitrile (2×5 mL) to provide the title compound (yield: 311 mg) as acolorless solid.

¹H NMR (500 MHz, DMSO-d₆) δ: 7.89 (d, J=8.7 Hz, 1H), 5.48 (m, 1H), 5.29(m, 1H), 4.30 (m, 1H), 4.02 (m, 1H), 3.73 (m, 1H), 3.43 (m, 1H), 3.15(m, 1H), 2.41 (m, 1H), 1.82 (s, 3H), 1.63 (m, 1H), 1.59 (dd, J=6.8, 1.9Hz, 3H), 1.55 (m, 1H), 1.27 (m, 1H), 0.85 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=285, (M+Na)+=307, (M−H)−=283.

EXAMPLE 43(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0065 g, 100%).

¹H NMR (DMSO-d₆) δ 7.90 (d, J=8.8 Hz, 1H), 5.47 (m, 1H), 5.29 (t, J=9.8Hz, 1H), 4.29 (t, J=8.8 Hz, 1H), 4.02 (q, J=6.8 Hz, 1H), 3.71 (bt, J=8Hz, 1H), 3.43 (m, 1H), 3.15 (quint., J=8.8 Hz, 1H), 2.41 (dt, J=12.7,7.8 Hz, 1H), 1.82 (s, 3H), 1.64 (m, 1H), 1.58 (dd, J=6.8, 1.5 Hz, 3H),1.53 (m, 1H), 0.85 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=285, (M+Na)+=307, (M−H)⁻=283, (M+CF₃COOH)⁻=397, (2M−1)⁻=563.

EXAMPLE 44(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-cyanopropyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

44A (±)-(2R,3S,5R,1′R,2′R) and(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (150 mg, 0.37 mmol) in THF (10 mL) was added dropwiseto a solution of the lithium enolate of acetonitrile (1.83 mmol, 5equivalents) in THF (15 mL) at −78° C. and reacted for 15 minutes. Thereaction was quenched with saturated aqueous ammonium chloride (10 mL)and water (10 mL) followed by extraction using dichloromethane (2×50mL). The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 2/1: ethyl acetate/hexane to provide the titlecompounds (±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl2-(1-acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 95mg, 58%) and(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl2-(1-acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 30 mg, 18%) as a colorless oils.

(±)-(2R,3S,5R,1′R,2′R)=MS: (M+H)⁺=452, (M−H)⁻=450.

(±)-(2R,3S,5R,1′R,2′S)=¹H NMR (CDCl₃) δ 8.14 (d, J=8.9 Hz, 1H), 5.51 (m,1H), 5.38 (m, 1H), 4.25 (m, 1H), 4.19 (m, 1H), 3.94 (m, 1H), 3.74 (m,1H), 3.22 (m, 1H), 2.54 (m, 1H), 2.47 (m, 2H), 2.04 (s, 3H), 1.69 (m,1H), 1.65 (dd, J=6.5, 1.8 Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H).

MS: (M+H)⁺=452, (M−H)⁻=450.

44B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4.5 mg, 95%).

¹H NMR (DMSO-d₆) δ 7.98 (d, J=10.0 Hz, 1H), 5.49 (m, 1H), 5.27 (m, 1H),4.30 (m, 1H), 4.15 (m, 1H), 3.75 (m, 1H), 3.18 (m, 1H), 2.72-2.58 (m,2H), 2.41 (m, 1H), 1.85 (s, 3H), 1.65 (m, 1H), 1.61 (dd, J=6.70, 1.80Hz, 3H).

MS: (M+H)⁺=296, (M−H)⁻=294.

EXAMPLE 45(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-cyano)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 8 mg, 95%).

¹H NMR (DMSO-d6) δ 7.75 (d, J=9.0 Hz, 1H), 5.47 (m, 1H), 5.25 (m, 1H),4.46 (m, 1H), 4.20 (m, 1H), 4.13 (m, 1H), 3.56 (m, 1H), 3.15 (m, 1H),2.55 (m, 2H), 2.42 (m, 1H), 1.82 (s, 3H), 1.72 (m, 1H), 1.55 (dd,J=6.71, 1.83, 3H).

MS: (M+H)⁺=296, (M+23)⁺=318, (M−H)⁻=294.

EXAMPLE 46(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

46A (±)-(2R,3S,5R,1′R,2′R) and(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (900 mg, 2.187 mmol) in THF (40 mL) was addeddropwise to a solution of the lithium enolate of ethyl acetate (8.75mmol, 4 equivalents) in THF (40 mL) at −78° C. and reacted for 15minutes. The reaction was quenched with saturated aqueous ammoniumchloride followed by extraction using dichloromethane (3×). The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica gelusing 1:1 ethyl acetate/hexane to provide the title compounds(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 690 mg, 63%) and(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 246 mg, 22.5%).

(±)-(2R,3S,5R,1′R,2′R) ¹H NMR (CDCl₃): δ 5.99 (d, 1H), 5.60 (m, 1H),5.36 (m, 1H), 4.81 (m, 1H), 4.15 (m, 4H), 3.74 (m, 1H), 3.07 (m, 1H),2.68 (m, 1H), 2.48 (m, 1H), 2.33 (m, 1H), 2.03 (s, 3H), 1.54 (dd, 3H),1.47 (s, 9H), 1.46 (s, 9H), 1.24 (t, J=7.5 Hz, 3H).

MS: (M+H)⁺=499.

(±)-(2R,3S,5R,1′R,2′S) ¹H NMR (CDCl₃): δ 7.93 (d, 1H), 5.44 (m, 2H),4.19 (m, 4H), 4.03 (m, 1H), 3.72 (m, 1H), 3.37 (m, 1H), 2.63 (m, 1H),2.48 (m, 2H), 2.01 (s, 3H), 1.65 (dd, 3H), 1.48 (s, 9H), 1.46 (s, 9H),1.26 (t, J=7.5 Hz, 3H).

MS: (M+H)⁺=499.

46B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 7.74 (d, J=9 Hz, 1H), 5.48 (m, 1H), 5.25 (m, 1H),4.43 (m, 1H), 4.24 (m, 1H), 4.14 (m, 1H), 4.06 (q, J=7.5 Hz, 2H), 3.54(m, 1H), 3.16 (m, 1H), 2.41 (m, 1H), 2.36 (m, 2H), 1.82 (s, 3H), 1.77(m, 1H), 1.56 (dd, 3H), 1.18 (t, J=7.5 Hz, 3H).

MS: (M+H)⁺=343.

EXAMPLE 47(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound is prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 7.93 (d, J=9 Hz, 1H), 5.48 (m, 1H), 5.30 (m, 1H),4.19 (m, 1H), 4.09 (m, 1H), 4.06 (q, J=7.5 Hz, 2H), 3.94 (m, 1H), 3.73(m, 1H), 3.18 (m, 1H), 2.54 (dd, 1H), 2.40 (m, 1H), 2.27 (m, 1H), 1.82(s, 3H), 1.65 (m, 1H), 1.60 (dd, 3H), 1.19 (t, J=7.5 Hz, 3H).

MS: (M+H)⁺=343.

EXAMPLE 48

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0030 g, 100%).

¹H NMR (DMSO-d₆) d 8.97 (bs, 1H), 7.88 (d, J=8.5 Hz, 1H), 5.45 (m, 1H),5.28 (t, J=9.1 Hz, 1H), 4.30 (t, J=8.6 Hz, 1H), 3.94 (q, J=7.3 Hz, 1H),3.71 (t, J=8.0 Hz, 1H), 3.62 (m, 1H), 3.15 (quint., J=9.0 Hz, 1H), 2.40(dt, J=12.8, 7.6 Hz, 1H), 1.83 (s, 3H), 1.65 (m, 1H), 1.59 (dd, J=7.0,1.5 Hz, 3H), 1.08 (d, J=5.5 Hz, 3H).

MS: (M+H)⁺=271, (M+Na)+=293, (M−H)⁻=269.

EXAMPLE 49

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0143 g, 100%).

¹H NMR (DMSO-d₆) δ 7.70 (d, J=9.1 Hz, 1H), 5.49 (m, 1H), 5.25 (t, J=9.1Hz, 1H), 4.43 (t, J=8.6 Hz, 1H), 4.03 (m, 1H), 3.92 (m, 1H), 3.55 (t,J=8.5 Hz, 1H), 3.17 (quint., J=8.5 Hz, 1H), 2.42 (dt, J=12.8, 7.3 Hz,1H), 1.85 (s, 3H), 1.72 (dt, J=12.8, 10.0 Hz, 1H), 1.57 (dd, J=6.7, 1.8Hz, 3H), 1.04 (d, J=6.1 Hz, 3H).

MS: (M+H)⁺=271, (M+Na)⁺=293, (M−H)⁻=269.

EXAMPLE 50(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

50A (±)-(2R,3S,5R,1′R,2′S) and(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B, substituting vinyl magnesium bromide for ethyl magnesiumbromide to provide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6.5 mg, 18%) and(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 22 mg, 59%).

(±)-(2R,3S,5R,1′R,2′S) MS: (M+H)⁺=439, (M−H)⁻=437.

(±)-(2R,3S,5R,1′R,2′R) MS: (M+H)⁺=439, (M−H)⁻=437.

50B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 5 mg, 96%).

¹H NMR (DMSO-d₆) δ 7.85 (d, J=9.1 Hz, 1H), 5.76 (m, 1H), 5.47 (m, 1H),5.25 (m, 2H), 5.14 (m, 1H), 4.29 (m, 1H), 4.05 (m, 1H), 3.96 (m, 1H),3.71 (m, 1H), 3.18 (m, 1H), 2.41 (m, 1H), 1.78 (s, 3H), 1.64 (m, 1H),1.59 (dd, J=6.71, 1.21 Hz, 3H)

MS: (M+H)⁺=283, (M+23)⁺=305, (M−H)⁻=281.

EXAMPLE 51

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6 mg, 95%).

¹H NMR (DMSO-d₆) δ 7.84 (d, J=9.7 Hz, 1H), 5.78 (m, 1H), 5.48 (m, 1H),5.23 (m, 34.43 (m, 1H), 4.26 (m, 1H), 4.20 (m, 1H), 3.55 (m, 1H), 3.18(m, 1H), 2.43 (m, 1H), 1.81 (s, 3H), 1.73 (m, 1H), 1.57 (dd, J=6.72,1.83 HZ, 3H).

MS: (M+H)⁺=283, (M+23)⁻=305, (M−H)⁻=281, (2M−H)⁻=563.

EXAMPLE 52(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

52A (±)-(2R,3S,5R,1′R,2′S) and(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B, substituting allyl magnesium bromide for ethyl magnesiumbromide to provide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2.0 mg, 5%) and(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 9.0 mg, 22%).

(±)-(2R,3S,5R,1′R,2′S) MS: (M+H)⁺=453; (M−H)⁻=451.

(±)-(2R,3S,5R,1′R,2′R) ¹H NMR (DMSO-d₆) δ 7.70 (d, J=9.3 Hz, 1H), 5.80(m, 1H), 5.51 (m, 1H), 5.30 (m, 1H), 5.00 (m, 2H), 4.58 (br d, 1H), 3.93(m, 2H), 3.50 (m, 1H), 3.22 (br t, 1H), 2.02 (m, 3H), 1.88 (s, 3H), 1.56(m, 4H), 1.41 (s, 9H), 1.36 (s, 9H)

MS: (M−H)⁻=451; (M+H)⁺=452, (M+Na)⁺=475.

52B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.85 (d, J=9.3 Hz, 1H), 5.81 (m, 1H), 5.42 (m, 1H),5.28 (t, J=7.3 Hz, 1H), 5.01 (br d, 2H), 3.99 (m, 2H), 3.57 (m, 2H),3.08 (m, 1H), 2.33 (m, 1H), 2.26 (m, 1H), 2.07 (m, 1H), 1.81 (s, 3H),1.57 (dd, J=1.4, 5.4 Hz, 4H).

MS: (M−H)⁻=295; (M+H)⁺=297, (M+Na)⁺=319.

EXAMPLE 53

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.68 (d, J=9.2 Hz, 1H), 5.78 (m, 1H), 5.48 (m, 1H),5.24 (t, J=7.8 Hz, 1H), 5.04 (m, 2H), 4.38 (t, J=7.0, 1H), 4.09 (t,J=7.0, 1H), 3.81 (t, J=4.7, 1H), 3.53 (t, J=8.5, 1H), 3.16 (m, 1H), 2.40(m, 1H), 2.11 (m, 2H), 1.83 (s, 3H), 1.70 (m, 1H), 1.55 (dd, J=5.4, 1.4Hz, 3H).

MS: (M−H)⁻=295; (M+H)⁺=297, (M+Na)⁺=319.

EXAMPLE 54(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

54A (±)-(2R,3S,5R,1′R,2′S) and(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B, substituting propyl magnesium bromide for ethyl magnesiumbromide to provide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 1 mg, 1%) and(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 32 mg, 39%).

(±)-(2R,3S,5R,1′R,2′S) ¹H NMR (CDCl₃) δ 7.51 (d, J=8.2 Hz, 1H), 5.46 (m,2H), 4.17 (dd, J=3.1, 6.8 Hz, 1H), 4.05 (m, 1H) 3.81 (t, J=3.4 Hz, 1H),3.54 (m, 1H), 3.21 (m, 1H), 2.60 (m, 1H), 2.02 (s, 3H), 1.70 (dt, J=3.0,7.4 Hz, 1H), 1.61 (d, J=5.4 Hz, 3H), 1.54 (m, 1H), 1.47 (s, 9H), 1.44(s, 9H), 1.32 (m, 4H), 0.90 (t, J=7.1 Hz, 3H).

MS: (M+H)⁺=455, (M+Na)⁺=477; (M−H)⁻=453.

(±)-(2R,3S,5R,1′R,2′R) ¹H NMR (CDCl₃) δ 5.98 (d, J=9.5 Hz, 1H), 5.60 (t,J=9.8 Hz, 1H), 5.36 (m, 1H), 4.16 (m, 1H), 3.75 (d, J=10.1 Hz, 1H), 3.64(m, 1H), 3.51 (m, 1H), 3.09 (br t, 1H), 2.68 (m, 1H), 2.02 (s, 3H), 1.81(d, J=13.9 Hz, 1H), 1.57 (m, 4H), 1.54 (dd, J=1.7, 5.1 Hz, 3H), 1.46 (s,9H), 1.45 (s, 9H), 0.88 (t, J=6.8 Hz, 3H).

MS: (M−H)⁻=453; (M+H)⁺=455.

54B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 1 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.83 (d, J=9.2 Hz, 1H), 5.43 (m, 1H), 5.23 (m, 1H),3.98 (m, 1H), 3.56 (br t, 1H), 3.46 (m, 1H), 3.08 (m, 2H), 2.32 (m, 1H),1.80 (s, 3H), 1.57 (dd, J=1.4, 5.4 Hz, 4H), 1.43 (m, 2H), 1.23 (m, 2H),0.85 (br t, 3H).

MS: (M+H)⁺=299, (M+Na)⁺=321.

EXAMPLE 55

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0190 g, 100%).

¹H NMR (DMSO-d₆) δ 7.64 (d, J=9.3 Hz, 1H), 5.48 (m, 1H), 5.24 (m, 1H),4.38 (t, J=8.8 Hz, 1H), 4.06 (m, 1H), 3.75 (m, 1H), 3.53 (t, J=8.5 Hz,1H), 3.16 (quint., J=8.5 Hz, 1H), 2.41 (dt, J=12.8, 7.3 Hz, 1H), 1.82(s, 3H), 1.70 (dt, 12.8, 9.9 Hz, 1H), 1.55 (dd, J=7.0, 1.6 Hz, 3H), 1.35(m, 2H), 1.26 (m, 2H), 0.86 (t, J=6.7 Hz, 3H).

MS: (M+H)⁺=299, (M+Na)⁺=321, (M−H)⁻=297.

EXAMPLE 56(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

56A (±)-(2R,3S,5R,1′R,2′S) and(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B, substituting isopropyl magnesium bromide for ethylmagnesium bromide to provide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0092 g, 10%) and(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0385 g, 40%).

(±)-(2R,3S,5R,1′R,2′S) MS: (M+H)⁺=455, (M+Na)⁺=477, (2M+Na)⁺=931,(M−H)⁻=453.

(±)-(2R,3S,5R,1′R,2′R) MS: (M+H)⁺=455, (M+Na)⁺=477, (2M+Na)⁺=931,(M−H)⁻=453.

56B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.010 g, 100%).

¹H NMR (DMSO-d₆) d 7.63 (d, J=9.2 Hz, 1H), 5.48 (m, 1H), 5.23 (m, 1H),4.44 (m, 1H), 4.24 (m, 1H), 3.57 (t, J=8.7 Hz, 1H), 3.33 (dd, J=8.5, 2.5Hz, 1H), 3.21 (quint., J=9.1 Hz, 1H), 2.43 (dt, J=12.8, 7.6 Hz, 1H),1.81 (s, 3H), 1.73 (dt, J=12.8, 10.4 Hz, 1H), 1.56 (dd, J=6.7, 1.9 Hz,3H), 1.55 (m, 1H), 0.94 (d, J=6.7 Hz, 3H), 0.78 (d, J=6.7 Hz, 3H).

MS: (M+H)⁺=299, (M+Na)⁺=321, (M−H)⁻=297, (M+CF₃COOH)⁻=411, (2M−H)⁻=595.

EXAMPLE 57

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0433 g, 100%).

¹H NMR (DMSO-d₆) d 7.88 (d, J=9.2 Hz, 1H), 5.46 (m, 1H), 5.29 (m, 1H),4.26 (t, J=8.5 Hz, 1H), 4.11 (m, 1H), 3.67 (m, 1H), 3.39 (dd, J=9.8, 1.8Hz, 1H), 3.15 (quint., J=9.1 Hz, 1H), 2.42 (dt, J=12.8, 7.9 Hz, 1H),1.81 (s, 3H), 1.73 (m, 1H), 1.62 (m, 1H), 1.57 (dd, J=7.0, 1.6 Hz, 3H),0.88 (d, J=6.7 Hz, 3H), 0.75 (d, J=6.7 Hz, 3H).

MS: (M+H)⁺=299, (M+Na)⁺=321, (M−H₂O)⁺=281, (M−H)⁻=297, (M+CF₃COOH)⁻=411,(2M−H)⁻=595.

EXAMPLE 58(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

58A (±)-(2R,3S,5R,1′R,2′S) and(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B, substituting butyl magnesium bromide for ethyl magnesiumbromide to provide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2.0 mg, 8%) and(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6.0 mg, 24%).

58B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid 1-butyl ester (yield: 2.0 mg, 100%).

¹H NMR (DMSO-d₆) δ 8.34 (d, J=9.3 Hz, 1H), 5.24 (m, 1H), 5.12 (m, 1H),3.90 (m, 1H), 3.78 (m, 1H), 3.23 (m, 1H), 2.90 (m, 1H), 2.14 (m, 1H),1.80 (m, 1H), 1.75 (s, 3H), 1.52 (m, 3H), 1.45 (m, 1H), 1.08 (br s, 6H),0.83 (br t, 3H).

MS: (M−H)⁻=311; (M+H)⁺=313.

EXAMPLE 59

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)hexyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6.0 mg, 100%).

¹H NMR DMSO-d₆) δ 7.60 (d, J=9.3 Hz, 1H), 5.46 (m, 1H), 5.24 (t, J=9.2Hz, 1H), 4.21 (t, J=8.3 Hz, 1H), 4.02 (t, J=7.9 Hz, 1H), 3.74 (m, 1H),3.47 (t, J=8.8, 1H), 3.12 (m, 1H), 2.37 (m, 1H), 1.81 (s, 3H), 1.64 (m,1H), 1.55 (dd, J=1.5, 5.4 Hz, 3H), 1.29 (m, 6H), 0.86 (t, J=6.9, 3H).

MS: (M−H)⁻=311; (M+H)⁺=313, (M+Na)⁺=335.

EXAMPLE 60(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

60A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B, substituting isobutyl magnesium bromide for ethyl magnesiumbromide to provide(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 31 mg, 51%).

(±)-(2R,3S,5R,1′R,2′R) ¹H NMR (CDCl₃) δ 5.98 (d, J=9.5 Hz, 1H), 5.61 (t,J=8.2 Hz, 1H), 5.35 (m, 1H), 4.51 (dd, J=1.3, 3.1 Hz, 1H), 4.15 (m, 1H),3.74 (d, J=10.5 Hz, 1H), 3.61 (m, 2H), 3.09 (t, J=7.5 Hz, 1H), 2.71 (m,1H), 2.02 (s, 3H), 1.81 (d, J=13.9 Hz, 1H), 1.58 (br s, 1H), 1.54 (dd,J=1.7, 5.1 Hz, 3H), 1.47 (s, 9H), 1.45 (s, 9H), 1.42 (m, 1H), 0.87 (dd,J=2.4, 6.7 Hz, 6H).

MS: (M−H)⁻=467; (M+H)⁺=469, (M+Na)⁺=491.

60B(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-4-methyl-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (8.0 mg, 0.02 mmol) was reacted with Dess-MartinPeriodinane (10 mg, 0.03 mmol) in dichloromethane (0.1 mL) at roomtemperature for 1 hour. The reaction was quenched with 1 M aqueoussodium thiosulfate 1 mL and stirred for 20 minutes. The reaction wasextracted with dichloromethane (3×1 mL). The organic layer was driedover magnesium sulfate, filtered, and concentrated in vacuo. The residuewas purified by column chromatography on silica gel using 1:1: ethylacetate/hexane to provide the title compound as a colorless semi-solid(yield: 4.8 mg, 61%).

60C(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-4-methyl-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (4.8 mg, 0.01 mmol) in methanol (0.1 mL) was reactedwith sodium borohydride (2.0 mg, 0.05 mmol) at room temperature for 0.5hours. The solvent was removed in vacuo and water (1 mL) was added. Theaqueous layer was extracted with dichloromethane (3×1 mL). This organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica gelusing 1:1 ethyl acetate/hexane to provide the title compound(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2.4 mg, 51%).

60B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4.4 mg, 100%).

¹H NMR (D₂O) δ 5.45 (m, 1H), 5.15 (t, J=11.0 Hz, 1H), 3.88 (m, 1H), 3.62(t, J=8.0 Hz, 1H), 3.43 (br t, 1H), 2.98 (m, 1H), 2.36 (m, 1H), 1.81 (s,3H), 1.60 (m, 1H), 1.51 (m, 1H), 1.45 (dd, J=1.3, 5.4 Hz, 3H), 1.17 (m,3H), 0.74 (dd, J=6.7, 14 Hz, 6H).

MS: (M−H)⁻=311; (M+H)⁺=313, (M+Na)⁺=335.

EXAMPLE 61

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 1.7 mg, 85%).

¹H NMR (DMSO-d₆) δ 7.61 (d, J=9.8 Hz, 1H), 5.45 (m, 1H), 5.24 (t, J=7.4Hz, 1H), 4.29 (br t, 1H), 4.0 (br t, 1H), 3.83 (m, 1H), 3.49 (t, J=8.8Hz, 1H), 3.13 (m, 1H), 2.39 (m, 1H), 1.82 (s, 3H), 1.68 (m, 2H), 1.55(dd, J=1.4, 5.4 Hz, 3H), 1.31 (m, 1H), 1.04 (m, 1H), 0.86 (dd, J=6.4,8.3 Hz, 6H).

MS: (M−H)⁻=311; (M+H)⁺=313, (M+Na)⁺=335.

EXAMPLE 62(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pent-3-ynyl)-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

62A (±)-(2R,3S,5R,1′R,2′S) and(±)-(2R,S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy)pent-3-vinyl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B substituting propyn-1-yl zinc for ethyl magnesium bromide toprovide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pent-3-ynyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0073 g, 16%) and(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pent-3-ynyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0349 g, 77%).

(±)-(2R,3S,5R,1′R,2′S) MS: (M+H)⁺=451, (M+Na)⁺=473, (2M+Na)⁺=923,(M−H)⁻=449.

(±)-(2R,3S,5R,1′R,2′R) MS: (M+H)⁺=451, (M+Na)⁺=473, (2M+Na)⁺=923,(M−H)⁻=449.

62B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pent-3-ynyl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pent-3-ynyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0052 9.100%).

¹H NMR (DMSO-d₆) d 7.97 (d, J=8.3 Hz, 1H), 5.48 (m, 1H), 5.25 (m, 1H),4.35-4.20 (m, 3H), 3.67 (m, 1H), 3.18 (quint., 8.8 Hz, 1H), 2.41 (dt,J=12.7, 7.8 Hz, 1H), 1.84 (s, 3H), 1.81 (d, J=1.9 Hz, 3H), 1.63 (m, 1H),1.59 (dd, J=6.9, 2.0 Hz, 3H).

MS: (M+H)⁺=295, (M+Na)⁺=317, (M−H)⁻=293, (M+CF₃COO⁻)⁻=407, (2M−H)⁻=587.

EXAMPLE 63

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)pent-3-ynyl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pent-3-ynyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0540 g, 100%).

¹H NMR (DMSO-d₆) d 7.90 (d, J=8.8 Hz, 1H), 5.50 (m, 1H), 5.25 (m, 1H),4.404.35 (m, 2H), 4.28 (m, 1H), 3.71 (t, J=8.0 Hz, 1H), 3.18 (quint.,8.3 Hz, 1H), 2.42 (dt, J=13.2, 7.4 Hz, 1H), 1.87 (s, 3H), 1.82 (d, J=1.9Hz, 3H), 1.71 (dt, J=12.7, 10.0 Hz, 1H), 1.57 (dd, J=6.9, 1.5 Hz, 3H).

MS: (M+H)⁺=295, (M+Na)⁺=317, (M−H)⁻=293, (M+CF₃COO⁻)⁻=407.

EXAMPLE 64(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-heptafluoroproyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

64A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (41 mg, 0.10 mmol) and heptafluoropropyl iodide(0.144 mL, 1.0 mmol, 10 equivalents) in THF (2 mL) were reacted with 1Mphenylmagnesium bromide (0.90 mL, 0.90 mmol, 9 equivalents) at −78° C.for 5 minutes. The reaction mixture was allowed to warm to roomtemperature over 1 h. The reaction was quenched with saturated aqueousammonium chloride (10 mL) and water (10 mL) followed by extraction usingethyl acetate (3×25 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel using 1/2: ethyl acetate/hexane toprovide the title compound (±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl2-(1-acetamido-2-hydroxy-2-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 12.6 mg, 22%).

(±)-(2R,3S,5R,1′R,2′R) MS: (M+H)⁺=581, (M+Na)⁺=603, (2M+Na)⁺=1183,(M−H)⁻=579.

64B(1)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-heptafluoropropyl)ethyl-3-(cis-propen-1-)l)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.003 g, 100%).

¹H NMR (DMSO-d₆) d 7.84 (d, J=9.3 Hz, 1H), 5.45 (m, 1H), 5.26 (m, 1H),4.71 (t, J=9.7 Hz, 1H), 4.63 (d, J=22.0 Hz, 1H), 4.51 (m, 1H), 3.59 (t,J=9.3 Hz, 1H), 3.19 (quint., 8.3 Hz, 1H), 2.43 (dt, J=12.7, 7.3 Hz, 1H),1.76 (s, 3H), 1.74 (m, 1H), 1.53 (dd, J=6.8, 1.4 Hz, 3H).

MS: (M+H)⁺=425, (M+Na)⁺=447, (M−H)⁻=423, (2M−1)⁻=847.

EXAMPLE 65 (±)-(2R3S,5R,1′R,2′S)-2-(1-Acetamido-2,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

65A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (35 mg, 0.07 mmol) was reacted with lithiumborohydride (8 mg, 0.35 mmol) in THF (5 mL) at 25° C. and reacted for 3hours. The reaction was quenched with saturated aqueous ammoniumchloride (2 mL) and water (2 mL) followed by extraction usingdichloromethane (2×10 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel using 5% methanol in dichloromethaneto provide the title compound (±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl2-(1-acetamido-2,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 14 mg, 44%).

(±)-(2R,3S,5R,1′R,2′S)=MS: (M+H)⁺=457, (M−H)⁻=455.

65B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2,4-dihydroxy)butyl3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in placeof(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆) δ 7.93 (d, J=9.0 Hz, 1H), 5.56 (m, 1H), 5.31 (m, 1H),4.43 (m, 1H), 4.14 (m, 1H), 3.69 (m, 1H), 3.63 (m, 1H), 3.23 (m, 2H),3.07 (m, 1H), 2.43 (m, 1H), 2.06 (s, 3H), 1.83 (m, 2H), 1.79 (m, 1H),1.62 (dd, J=6.71, 1.22 Hz, 3H).

MS: (M+H)⁺=301, (M−H)⁻=299.

EXAMPLE 66(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

66A(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 65A substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethoxycarbonyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 11 mg, 70%).

¹H NMR (CDCl₃) δ 5.58 (m, 1H), 5.38 (m, 1H), 4.16 (m, 1H), 4.05 (m, 1H),3.97 (m, 1H), 3.78 (m, 2H), 3.20 (m, 1H), 2.66 (m, 1H) 2.54 (m, 1H),2.04 (s, 3H), 1.80 (m, 1H), 1.55 (m, 2H), 1.47 (s, 9H), 1.44 (s, 9H).

MS: (M+H)⁺=457, (M−H)⁻=455.

66B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2,4-dihydroxy)butyl3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acid t-butyl ester in placeof(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 8 mg, 96%).

¹H NMR (DMSO-d₆) δ 7.91 (d, J=9.1 Hz, 1H), 5.50 (m, 1H), 5.25 (m, 1H),4.43 (m, 1H), 4.30 (m, 1H), 4.22 (m, 1H), 3.94 (m, 1H), 3.86 (m, 1H),3.62 (m, 1H), 3.18 (m, 1H), 2.43 (m, 1H), 1.85 (s, 3H), 1.75 (m, 1H),1.65 (m, 2H), 1.58 (dd, J=6.70, 1.81 Hz, 3H).

MS: (M+H)⁺=301, (M−H)⁻=299.

EXAMPLE 67(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

67A (±)-(2R,3S,5R,1′R,2′R) and(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B, substituting lithium phenylacetylide for ethyl magnesiumbromide to provide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0010 g, 4%) and(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-phenylacetylen-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0050 g, 21%).

(±)-(2R,3S,5R,1′R,2′S) MS: (M+H)⁺=513, (M+Na)⁺=535, (2M+Na)⁺=1047,(M−H)⁻=511.

(±)-(2R,3S,5R,1′R,2′R) MS: (M+H)⁺=513, (M+Na)⁺=535, (2M+Na)⁺=1047,(M−H)⁻=511.

67B (±)-(2R3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound is prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 68(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

68A(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(phenylacetylen-1-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0034 g, 100%).

¹H NMR (DMSO-d₆) δ 9.2 (bs, 1H), 8.04 (d, J=9.2 Hz, 1H), 7.45-7.35 (m,5H), 5.50 (m, 1H), 5.29 (m, 1H), 4.64 (d, J=4.9, 1H), 4.5-4.4 (m, 2H),3.81 (m, 1H), 3.22 (quint., J=8.5 Hz, 1H), 2.45 (dt, J=12.8, 7.3 Hz,1H), 1.89 (s, 3H), 1.74 (dt, J=12.7, 10.0 Hz, 1H), 1.58 (dd, J=7.3, 1.8Hz, 3H).

MS: (M+H)⁺=357, (M+Na)⁺=379, (M−H)⁻=355.

EXAMPLE 69(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

69A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42A, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 8 mg, 81%).

MS: (M+H)⁺=481, (M−H)⁻=479.

69B(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42B, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of (2R,3S,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 5 mg, 63%).

MS: (M+H)⁺=483, (M−H)−=481.

69C(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4 mg, 95%).

¹H NMR (DMSO-d₆) δ 7.67 (d, J=8.9 Hz, 1H), 5.48 (m, 1H), 5.23 (m, 1H),4.42 (m, 1H), 4.21 (m, 1H), 1.74 (m, 1H), 1.58 (dd, J=6.71, 1.23 Hz,3H), 1.52 (m, 1H), 1.38 (m, 1H), 1.29 (m, 2 Hz), 1.13 (m, 1H), 0.80 (m,6H).

MS: (M+H)⁺=327, (M−H)⁻=325.

EXAMPLE 70(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

70A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 41B, substituting 3-pentyl magnesium bromide in place of ethylmagnesium bromide (yield: 13mg, 45%).

MS: (M+H)⁺=483, (M−H)⁻=481.

70B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-ethyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3 mg, 96%).

¹H NMR (DMSO-d₆) δ 7.85 (d, J=9.2 Hz, 1H), 5.47 (m, 1H), 5.30 (m, 1H),4.28 (m, 1H), 4.19 (m, 1H), 3.67 (m, 1H), 3.58 (m, 1H), 3.17 (m, 1H),2.43 (m, 1H), 1.81 (s, 3H), 1.63 (m, 1H), 1.58 (dd, J=6.71, 1.82 Hz,3H), 1.40 (m, 2H), 1.28 (m, 1H), 1.10 (m, 1H), 1.05 (m, 1H), 0.83 (m,6H).

MS: (M+H)⁺=327, (M−H)⁻=325.

EXAMPLE 71(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

71A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 41B, substituting phenyl magnesium bromide in place of ethylmagnesium bromide (yield: 36 mg, 60%).

MS: (M+H)⁺=489, (M+Na)+=511, (M−H)−=487.

71B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 5.5 mg, 100%).

¹H NMR (DMSO-d₆) d 7.79 (d, J=9.2 Hz, 1H), 7.36 (m, 2H), 7.31 (m, 2H),7.22 (m, 1H), 5.49 (m, 1H), 5.22 (m, 1H), 4.94 (d, J=3.0 Hz, 1H), 4.52(m, 1H), 4.35 (m, 1H), 3.62 (t, J=8.5 Hz, 1H), 3.22 (m, 1H), 2.46 (m,1H), 1.77 (m, 1H), 1.65 (s, 3H), 1.57 (dd, J=6.7, 0.8 Hz, 3H).

MS: (M+H)+=333, (M+Na)+=355, (M−H)−=331.

EXAMPLE 72(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

72A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42A, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of (2R,3S,5R,1′R,2′R)-t-butoxycarbonyl2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 24 mg, 84%).

MS: (M+H)⁺=487, (M+Na)⁺=509, (M−H)⁻=485.

72B(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42B, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of (2R,3S,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 7.9 mg, 52%).

MS: (M+H)⁺=489, (M+Na)⁺=520, (M−H)⁻=487.

72C(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 7.5 mg, 100%).

¹H NMR (DMSO-d₆) d 7.83 (d, J=9.2 Hz, 1H), 7.36 (m, 2H), 7.32 (m, 2H),7.25 (m, 1H), 5.47 (m, 1H), 5.33 (m, 1H), 4.54 (d, J=9.8 Hz, 1H), 4.36(m, 1H), 4.23 (m, 1H), 3.78 (m, 1H), 3.20 (m, 1H), 2.43 (m, 1H), 1.63(m, 1H), 1.56 (dd, J=6.7, 1.2 Hz, 3H), 1.53 (s, 3H).

MS: (M+H)⁺=333, (M+Na)⁺=355, (M−H)⁻=331.

EXAMPLE 73(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-(thiophen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

73A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(thiophen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (40 mg, 0.098 mmol) in THF (2 mL) was added dropwiseto a solution of 2-thienyllithium (1M in THF, 0.505 mmol, 5 equivalents)in THF (1 mL) at 25° C. and reacted for 20 minutes. The reaction wasquenched with saturated aqueous ammonium chloride (2 mL) and water (5mL) followed by extraction using dichloromethane (2×10 mL). The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica gelusing 1/1: ethyl acetate/hexane to provide the title compound (yield:9.5 mg, 20%).

MS: (M+H)⁺=495, (M+Na)⁺=517, (M−H)⁻=493.

73B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-(thiophen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(thiophen-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4.3 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.86 (d, J=9.8 Hz, 1H), 7.63 (dd, J=5.4, 1.0 Hz, 1H),7.07 (m, 1H), 6.98 (m, 1H), 5.58 (m, 1H), 5.43 (m, 1H), 4.55 (m, 1H),4.39 (m, 1H), 3.72 (m, 1H), 3.11 (m, 2H), 2.43 (m, 1H), 2.04 (s, 3H),1.80 (m, 1H), 1.57 (m, 3H).

MS: (M+H)⁺=339, (M+Na)+=361, (M−H)−=337.

EXAMPLE 74(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

74A (±)-(2R,3S,5R,1′R,2′S) and(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

1.6 M n-Butyllithium (0.125 mL, 0.20 mmol, 4 equivalents) was added to asolution of 2,4-dimethylthiazole (28.3 mg, 0.25 mmol, 5 equivalents) in1 mL of THF at −78° C. and reacted for 30 minutes.((±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (20.5 mg, 0.050 mmol) in THF (1 mL) was addeddropwise to the above solution and reacted for 30 minutes at −78° C. andthen for 30 minutes at room temperature. The reaction mixture wasquenched with saturated aqueous ammonium chloride (5 mL) and water (5mL) followed by extraction using dichloromethane (3×25 mL). The organiclayer was dried over magnesium sulfate, filtered and concentrated invacuo. The residue was purified by column chromatography on silica gelusing 1/2: ethyl acetate/hexane to provide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.3 mg, 13%) and(±)-(2R,3S,5R,1′R,2′R)-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 7.5 mg, 29%).

(2R,3S,5R,1′R,2′S) MS: (M+H)⁺=524, (M+Na)⁺=546, (2M+Na)⁺=1069,(M−H)⁻=522.

(2R,3S,5R,1′R,2′R) MS: (M+H)⁺=524, (M+Na)⁺=546, (2M+Na)⁺=1069,(M−H)⁻=522.

74B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0030 g, 100%).

¹H NMR (DMSO-d₆) δ 9.0 (bs, 1H), 8.10 (d, J=8.3 Hz, 1H), 7.11 (d, J=1.0Hz, 1H), 5.48 (m, 1H), 5.30 (m, 1H), 4.30 (m, 1H), 4.10 (m, 1H), 3.88(dt, J=9.4, 2.6 Hz, 1H), 3.78 (m, 1H), 3.25-3.15 (m, 2H), 2.93 (dd,J=15.1, 8.3 Hz, 1H), 2.41 (dt, J=12.3, 7.3 Hz, 1H), 2.33 (d, J=1.0 Hz,3H), 1.86 (s, 3H), 1.66 (dt, J=12.7, 10.3 Hz, 1H), 1.61 (dd, J=6.8, 1.5Hz, 3H).

MS: (M+H)⁺=368, (M+Na)+=390, (M−H)⁻=366.

EXAMPLE 75(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-(4-methylthiazol-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0030 g, 100%).

¹H NMR (DMSO-d₆) d 9.0 (bs, 1H), 7.77 (d, J=9.3 Hz, 1H), 7.11 (s, 1H),5.47 (m, 1H), 5.25 (m, 1H), 4.45 (m, 1H), 4.20 (m, 2H), 3.58 (t, J=9.1Hz, 1H), 3.19 (m, 1H), 2.96 (m, 2H), 2.41 (m, 1H), 2.33 (d, J=1.0 Hz,3H), 1.85 (s, 3H), 1.73 (dt, J=12.7, 10.3 Hz, 1H), 1.54 (dd, J=6.9, 1.5Hz, 3H).

MS: (M+H)⁺=368, (M+Na)+=390, (M−H)⁻=366, (M+CF₃COOH)⁻=480, (2M−H)⁻=733.

EXAMPLE 76(±)-(2R,3S,5R,1′R,2′RS)-2-(1-Acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

76A(±)-(2R,3S,5R,1′R,2′RS)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (20.5 mg, 0.05 mmol) in THF (1 mL) was added dropwiseto a solution of the (thiazolin-2-yl) methyl lithium (0.20 mmol, 4equivalents, prepared from 0.025 g of 2-methylthiazoline and 0.125 mL of1.6 M n-BuLi at −78° C.) in THF (2 mL) at −78° C. and reacted for 30minutes. The reaction was quenched with saturated aqueous ammoniumchloride (5 mL) and water (5 mL) followed by extraction usingdichloromethane (3×20 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel using 1/1: ethyl acetate/hexane toprovide the title compound as a mixture of isomers (yield: 10 mg, 40%).

MS: (M+H)⁺=512, (M+Na)⁺=534, (M−H)⁻=510.

76B(±)-(2R,3S,5R,1′R,2′RS)-2-(1-Acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidinecarboxylic Acid Trifluoroacetic Acid Salt

The title compounds were prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-(thiazolin-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester n place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.003 g, 100%).

Major isomer ¹H NMR (DMSO-d₆) δ 8.88 (m, 1H), 7.76 (d, J=8.8 Hz, 1H),5.46 (m, 1H), 5.19 (m, 1H), 4.69 (m, 1H), 3.90 (m, 1H), 3.85 (m, 1H),3.49 (m, 2H), 3.35 (t, J=9.0 Hz, 1H), 3.29 (dd, J=17.6, 5.9 Hz, 1H),3.04 (t, J=8.9 Hz, 1H), 2.78 (dd, J=17.6, 8.1 Hz, 1H), 2.7-2.55 (m, 2H),1.75 (s, 3H), 1.70 (m, 1H), 1.56 (dd, J=6.8, 1.5 Hz, 3H).

MS: (M+H)⁺=356, (M+Na)⁺=378, (2M+Na)⁺=733, (M−H)⁻=354.

EXAMPLE 77(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

77A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (41 mg, 0.10 mmol) and 1,1-difluoroallyl iodide (94mg, 0.60 mmol, 6 equivalents) in THF (2 mL) was reacted with zinc dust(33 mg, 0.50 mmol, 5 equivalents) at 0° C. for 5 minutes and then atroom temperature for 4 hours. The reaction mixture was quenched withsaturated aqueous ammonium chloride (15 mL) and water (15 mL) andextracted with 3×25 mL dichloromethane. The organic layer was dried overmagnesium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel using 1/3: ethylacetate/hexane to provide the title compound (yield: 35 mg, 71%).

MS: (M+H)⁺=489, (M+Na)⁺=511, (2M+Na)⁺=999, (M−H)⁻=487.

77B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0026 g, 96%).

¹H NMR (DMSO-d₆) d 7.68 (d, J=7.8 Hz, 1H), 5.97 (m, 1H), 5.55-5.45 (m,2H), 5.43 (m, 1H), 5.23 (m, 1H), 4.45 (m, 2H), 4.10 (m, 1H), 3.16(quint. J=9.1 Hz, 1H), 2.41 (dt, J=12.8, 7.3 Hz, 1H), 1.72 (s, 3H), 1.70(dt, J=12.8, 10.3 Hz, 1H), 1.61 (dd, J=6.7, 1.2 Hz, 3H).

MS: (M+H)⁺=333, (M+Na)⁺=355, (M−H)⁻=331, (2M−H)⁻=663.

EXAMPLE 78(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

78A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42A, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(2R,3S,5R,1′R,2′R)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester to provide(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-3,3-difluoro-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0050 g, 44%).

MS: (M+H)⁺=487, (M+Na)⁺=509, (M−2F)⁺=448, (M−H)⁻=485.

78B(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 42B, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(2R,3S,5R,1′R)-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

78C(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid

The title compound is prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 79(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-(cis-buten-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

79A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-2-(cis-buten-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (30 mg, 0.073 mmol) in THF (5 mL) was reacted withcis-2-buten-2-yl lithium (0.75 mL (0.5M), 0.37 mmol) at 25° C. for 45min. The reaction was quenched with saturated aqueous ammonium chloride(5 mL) and water (5 mL) followed by extraction using dichloromethane(2×10 mL). The organic layer was dried over magnesium sulfate, filteredand concentrated in vacuo. The residue was purified by columnchromatography on silica gel using 1/1: ethyl acetate/hexane to providethe title compound (yield: 20 mg, 59%).

¹H NMR (CDCl₃) δ 6.19 (d, J=8.9 Hz, 1H), 5.61 (m, 1H), 5.35 (m, 1H),5.27 (m, 1H), 4.48 (m, 1H), 4.18 (m, 1H), 4.77 (m, 2H), 3.10 (m, 1H),2.72 (m, 1H), 1.99 (s, 3H), 1.82 (m, 1H), 1.73 (m, 3H), 1.55 (m, 6H),1.47 (s, 9H), 1.44 (s, 9H).

MS: (M+H)⁺=467, (M−H)⁻=465.

79B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-(cis-buten-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-(cis-buten-2-yl))ethyl-3-(cis-propen-1-ylpyrrolidine-5-carboxylic acid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4 mg, 96%).

¹H NMR (DMSO-d₆) δ 8.09 (d, J=9.0 Hz, 1H), 5.50 (m, 1H), 5.32 (m, 1H),5.16 (m, 1H), 4.50 (m, 1H), 4.38 (m, 1H), 4.19 (m, 1H), 3.43 (m, 1H),3.20 (m, 1H), 2.43 (m, 1H), 1.88 (s, 3H), 1.74 (m, 1H), 1.70 (s, 3H),1.62 (m, 3H), 1.58 (m, 3H).

MS: (M+H)⁺=311, (M−H)⁻=309.

EXAMPLE 80 (±)-(2R,3S,5R,1′R,2′R,3′R) and(±)-(2R,3S,5R,1′R,2′R,3′S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

80A (±)-(2R,3S,5R,1′R,2′R,3′R) and(±)-(2R,3S,5R,1′R,2′R,3′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (60 mg, 0.15 mmol) in THF (1 mL) was added dropwiseto a solution of 2-butylmagnesium bromide (3M in ether) (0.45 mL, 0.85mmol) at room temperature and reacted for 40 minutes. The reaction wasquenched with saturated NH₄Cl (1 mL) followed by extraction usingdichloromethane (3×1 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel using 1/4: ethyl acetate/hexane toprovide the title compounds(±)-(2R,3S,5R,1′R,2′R,3′S)-1-t-butoxycarbonyl2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester R_(f)=0.65 (1:1 ethyl acetate:hexanes) (yield: 19 mg,27%) and (±)-(2R,3S,5R,1′R,2′R,3′R)-1-t-butoxycarbonyl2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester R_(f)=0.5) (1:1 ethyl acetate:hexanes) (yield: 19 mg,27%).

R_(f)=0.65 ¹H NMR (CDCl₃) δ 5.98 (d, J=8.8 Hz, 1H), 5.62 (t, J=10.5 Hz,1H), 5.35 (m, 1H), 4.66 (d, J=4.4 Hz, 1H), 4.16 (d, J=9.5 Hz, 1H), 3.78(m, 3H), 3.12 (m, 2H), 2.73 (m, 1H), 2.0 (s, 3H), 1.81 (d, J=13.2 Hz,1H), 1.54 (br s, 3H), 1.47 (s, 9H), 1.44 (s, 9H), 1.25 (m, 1H), 0.81 (m,6H).

MS: (M−H)⁻=467; (M+H)⁺=469.

R_(f)=0.5 ¹H NMR (CDCl₃) δ 6.00 (d, J=10.2 Hz, 1H), 5.61 (br t, 1H),5.36 (m, 1H), 4.58 (d, J=4.7 Hz, 1H), 4.14 (d, J=8.8 Hz, 1H), 3.82 (m,3H), 3.13 (m, 2H), 2.73 (m, 1H), 1.99 (s, 3H), 1.80 (d, J=13.9 Hz, 1H),1.54 (br s, 3H), 1.46 (s, 9H), 1.44 (s, 9H), 1.43 (m, 1H), 0.97 (d,J=6.8 Hz, 3H), 0.81 (t, J=7.2 Hz, 3H).

MS: (M−H)⁻=467; (M+H)⁺=469.

80B(±)-(2R,3S,5R,1′R,2′R,3′S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

(±)-(2R,3S,5R,1′R,2′R,3′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (2.5 mg, 0.005 mmol) was reacted with trifluoroaceticacid (0.8 mL) in dichloromethane (0.2 mL) at room temperature for 6 hrs.The reaction was concentrated in vacuo overnight and triturated withacetonitrile (2×1 mL) to provide the title compound (yield: 2.0 mg,100%).

¹H NMR (DMSO-d6) δ 7.68 (d, J=8.8 Hz, 1H), 5.45 (m, 1H), 5.23 (t, J=7.3Hz, 1H), 4.24 (br t, 1H), 4.18 (m, 1H), 3.52 (t, J=7.3 Hz, 1H), 3.45 (m,1H), 3.16 (m, 1H), 2.38 (m, 1H), 1.83 (s, 3H), 1.68 (m, 1H), 1.58 (dd,J=2.0, 4.8 Hz, 3H), 1.37 (m, 2H), 0.99 (m, 1H), 0.89 (d, J=6.8 Hz, 3H),0.79 (t, J=7.4 Hz, 3H).

MS: (M−H)−=311; (M+H)+=313, (M+Na)+=335.

EXAMPLE 81(±)-(2R,3S,5R,1′R,2′R,3′R)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R,3′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (R_(f)=0.5, 1:1, ethyl acetate:hexanes) in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 1.6 mg, 76%).

¹H NMR (DMSO-d₆) δ 7.55 (d, J=9.3 Hz, 1H), 5.45 (m, 1H), 5.23 (m, 1H),4.31 (br t, 1H), 4.20 (t, J=8.3 Hz, 1H), 3.51 (t, J=9.3 Hz, 1H), 3.43(d, J=7.4 Hz, 1H), 3.17 (m, 1H), 2.40 (m, 1H), 1.80 (s, 3H), 1.70 (m,1H), 1.55 (dd, J=1.4, 5.4 Hz, 3H), 1.36 (m, 2H), 1.14 (m, 1H), 0.84 (t,J=7.3 Hz, 3H), 0.73 (d, J=6.9 Hz, 3H).

MS: (M−H)⁻=311; (M+H)⁺=313, (M+Na)⁺=335.

EXAMPLE 82(±)-(2R,3S,5R,1′R,2′S,3′S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

82A(±)-(2R,3S,5R,1′R,3′RS)-1-t-Butoxycarbonyl-2-(1-acetamido-2-oxo-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42A, substituting(±)-(2R,3S,5R,1′R,2′R,3′RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of (±)-(2R,3S,5R,1′R,2′R)1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl (yield: 12 mg, 63%).

82B (±)-(2R,3S,5R,1′R,2′S,3′S) and(±)-(2R,3S,5R,1′R,2′S,3′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 42B, substituting(±)-(2R,3S,5R,1′R,3′RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (R_(f)=0.5 and 0.65, 1:1, ethyl acetate:hexanes) inplace of(2R,3S,5R,1′R)-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester to give(±)-(2R,3S,5R,1′R,2′S,3′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (R_(f)=0.15, 1:1, ethyl acetate:hexanes) (yield: 6.0mg, 50%) and(±)-(2R,3S,5R,1′R,2′S,3′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester(R_(f)=0.10, 1:1, ethyl acetate:hexanes) (yield: 2.5mg, 63%).

82C(±)-(2R,3S,5R,1′R,2′S,3′S)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S,3′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (R_(f)=0.15, 1:1, ethyl acetate:hexanes) in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6.0 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.78 (d, J=9.2 Hz, 1H), 5.42 (m, 1H), 5.29 (t, J=10.3Hz, 1H), 4.08 (m, 1H), 3.96 (br t, 1H), 3.51 (m, 2H), 3.08 (m, 1H), 2.33(m, 1H), 1.78 (s, 3H), 1.56 (d, J=6.3 Hz, 3H), 1.52 (m, 1H), 1.40 (m,1H), 1.29 (m, 1H), 1.21 (m, 1H), 0.84 (t, J=7.3 Hz, 3H), 0.73 (d, J=6.9Hz, 3H).

MS: (M−H)⁻=311; (M+H)⁺=313, (M+Na)⁺=335.

EXAMPLE 83(±)-(2R,3S,5R,1′R,2′S,3′R)-2-(1-Acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C,substituting(±)-(2R,3S,5R,1′R,2′S,3′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (R_(f)=0.10, 1:1 ethyl acetate:hexanes) in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2.5 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.85 (d, J=8.7 Hz, 1H), 5.45 (m, 1H), 5.29 (t, J=9.3Hz, 1H), 4.20 (m, 2H), 3.63 (t, J=8.3 Hz, 1H), 3.42 (br d, 1H), 3.14 (m,1H), 2.41 (m, 1H), 1.79 (s, 3H), 1.62 (m, 1H), 1.58 (d, J=5.4 Hz, 3H),1.43 (m, 2H), 1.0 (m, 1H), 0.88 (d, J=6.8 Hz, 3H), 0.80 (t, J=7.3 Hz,3H).

MS: (M−H)⁻=311; (M+H)⁺=313, (M+Na)⁺=335.

EXAMPLE 84(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

84A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (22 mg, 0.05 mmole) was reacted with methyl iodide(0.016 mL, 0.25 mmole), potassium hydroxide (14 mg, 0.25 mmole) and18-crown-6 (0.7 mg, 0.0025 mmole) in N,N-dimethylformamide (2 mL) atroom temperature for 23 hours. Water (5 mL) was then added to thereaction mixture, followed by extraction with ether (2×10 mL). Theorganic layer was washed with water, and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel using 66% ethyl acetate/hexanes to providethe title compound, as a colorless oil (yield: 5.2 mg, 23%).

MS: (M+H)⁺=455, (M−H)−=453.

84B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4.7 mg, 98%).

¹H NMR (DMSO-d6) δ 7.96 (d, J=9.2 Hz, 1H), 5.50 (m, 1H), 5.24 (m, 1H),4.25 (m, 2H), 3.70 (m, 1H), 3.23 (s, 3H), 3.19 (m, 2H), 2.40 (m, 2H),1.86 (s, 3H), 1.68 (m, 2H), 1.62 (dd, J=7.0, 1.8 Hz, 3H), 1.39 (m, 1H),0.77 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=299, (M+Na)+=297.

EXAMPLE 85(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

85A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (17 mg, 0.04 mmole) was reacted with methyl iodide(28 mg, 0. 19 mmole), potassium hydroxide (8 mg, 0.19 mmole) and18-crown-6 (0.002 mmole) in N,N-dimethylformamide (1.5 mL) at roomtemperature for 6 hours. Water (5 mL) was then added to the reactionmixture, followed by extraction with ether (2×10 mL) The organic layerwas washed with water, and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 50% ethyl acetate/hexanes to provide the titlecompound, (yield: 5 mg, 29%).

MS: (M+H)⁺=455, (M−H)⁻=453.

85B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4 mg, 95%).

¹H NMR (DMSO-d6) d 8.00 (d, J=9.8 HZ,1H), 5.57 (m, 1H), 5.35 (m, 1H),4.42 (m, 1H), 4.28 (m, 1H), 3.95 (m, 1H), 3.54 (m, 1H), 3.28 (s, 3H),2.80 (m, 1H), 2.30 (m, 1H), 1.92 (s, 3H), 1.65 (m, 1H), 1.60 (m, 3H),1.43 (m, 2H), 0.82 (t, J=7.31 HZ, 3H).

MS: (M+H)+=299, (M−H)−=297.

EXAMPLE 86(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

86A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound is prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

86B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound is prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 87(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

86A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6.8 mg, 33%).

MS: (M+H)⁺=469, (M+Na)⁺=491, (M−H)⁻=467.

87B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. ester (yield: 6.6 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.65 (d, J=9.2 Hz, 1H), 5.43 (m, 1H), 5.23 (m, 1H),4.42 (m, 1H), 4.37 (m, 1H), 3.56 (m, 1H), 3.46 (s, 3H), 3.17 (m, 2H),2.44 (m, 1H), 1.80 (s, 3H), 1.78 (m, 1H), 1.70 (m, 1H), 1.57 (dd, J=6.7,1.2 Hz, 3H), 0.94 (d, J=6.7 Hz, 3H), 0.82 (d, J=6.7 Hz, 3H).

MS: (M+H)⁺=313, (M+Na)+=335, (M−H−=311.

EXAMPLE 88(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

88A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 11.9 mg, 36%).

MS: (M+H)⁺=469, (M+Na)+=491, (M−H)−=467.

88B(±)-(2R,3.5R,1′R,2′S)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 11.5 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.95 (d, J=9.8 Hz, 1H), 5.49 (m, 1H), 5.23 (m, 1H),4.25 (m, 2H), 3.68 (m, 1H), 3.24 (s, 3H), 3.22 (m, 1H), 3.18 (m, 1H),2.40 (m, 1H), 1.85 (s, 3H), 1.66 (m, 1H), 1.62 (m, 3H), 1.58 (m, 1H),1.38 (m, 1H), 1.27 (m, 2H), 0.86 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=313, (M+Na)+=335, (M−H)−=311.

EXAMPLE 89(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

89A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4.3 mg, 21%).

MS: (M+H)⁺=469, (M+Na)⁺=491, (M−H)⁻=467.

89B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4.8 mg, 100%).

¹H NMR (DMSO-d₈) δ 7.70 (d, J=9.8 Hz, 1H), 5.45 (m, 1H), 5.24 (m, 1H),4.40 (m, 1H), 4.25 (m, 1H), 3.57 (t, J=8.5 Hz, 1H), 3.40 (m, 1H), 3.35(s, 3H), 3.17 (m, 1H), 2.42 (m, 1H), 1.82 (s, 3H), 1.69 (m, 1H), 1.56(dd, J=7.1, 1.2 Hz, 3H), 1.24 (m, 4H), 0.88 (t, J=7.0 Hz, 3H).

MS: (M+H)⁺=313, (M+Na)+=335, (M−H−=311.

EXAMPLE 90(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

90A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 8 mg, 31%).

MS: (M+H)⁺=467, (M−H)⁻=465.

90B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. ester (yield: 6 mg, 96%).

¹H NMR (DMSO-d₆) δ 8.02 (d, J=8.6 HZ, 1H), 5.75 (m, 1H), 5.51 (m, 1H),5.24 (m, 1H), 5.05 (m, 2H), 4.27 (m, 1H), 4.22 (m, 1H), 3.74 (m, 2H),3.26 (s, 3H), 3.18 (m, 1H), 2.47 (m, 1H), 2.39 (m, 1H), 2.17 (m, 1H),1.87 (s, 3H), 1.67 (m, 1H), 1.63 (dd, J=6.71, 1.23 HZ, 3H).

MS: (M+H)⁺=311, (M−H)⁻=309.

EXAMPLE 91(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

91A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4.0 mg, 16%).

MS: (M+H)⁺=467, (M−H)⁻=465.

91B (±)-(2R3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3 mg, 96%).

¹H NMR (DMSO-d₆) δ 7.75 (d, J=9.2 HZ, 1H), 5.75 (m, 1H), 5.47 (m, 1H),5.24 (m, 1H), 5.06 (m, 2H), 4.42 (m, 1H), 4.25 (m, 1H), 3.58 (m, 1H),3.50 (m, 1H), 3.37 (s, 3H), 3.17 (m, 1H), 2.42 (m, 1H), 2.36 (m, 1H),1.83 (s, 3H), 1.71 (m, 1H), 1.55 (dd, J=6.73, 1.83 HZ, 3H).

MS: (M+H)⁺=311, (M−H)⁻=309.

EXAMPLE 92(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

92A (±)-(2R,3S,5R,1′R,2′S) and(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B, substituting 1-buten-4-yl magnesium bromide for ethylmagnesium bromide to provide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0030 g, 6%) and(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0145 g, 28%).

(±)-(2R,3S,5R,1′R,2′S) MS: (M+H)⁺=467, (M+Na)⁺=489, (2M+Na)⁺=955,(M−H)⁻=465.

(±)-(2R,3S,5R,1′R,2′R)- MS: (M+H)⁺=467, (M+Na)⁺=489, (2M+Na)⁺=955,(M−H)⁻=465.

92B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0027 g, 100%).

¹H NMR (DMSO-d₆) δ 8.93 (bs, 1H), 7.90 (d, J=9.2 Hz, 1H), 5.80 (m, 1H),5.48 (m, 1H), 5.28 (m, 1H), 5.00 (dd, J=17.1, 1.8 Hz, 1H), 4.94 (dd,J=10.4, 1.8 Hz, 1H), 4.29 (bt, J=8.3 Hz, 1H), 4.03 (m, 1H), 3.71 (m,1H), 3.49 (m, 1H), 3.15 (quint., J=8.5 Hz, 1H), 2.41 (dt, J=12.8, 7.3Hz, 1H), 2.16 (m, 1H), 2.05 (m, 1H), 1.83 (s, 3H), 1.79-1.75 (m, 1H),1.64 (m, 1H), 1.58 (dd, J=6.7, 1.8 Hz, 3H), 1.34 (m, 2H).

MS: (M+H)⁺=311, (M+Na)⁺=333, (M−H)⁻=309, (M+CF₃COO⁻)⁻=423.

EXAMPLE 93(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

93A(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0027 g, 100%).

¹H NMR (DMSO-d₆) δ 7.68 (d, J=9.6 Hz, 1H), 5.81 (m, 1H), 5.48 (m, 1H),5.25 (m, 1H), 5.01 (dd, J=17.1, 1.8 Hz, 1H), 4.95 (dd, J=10.3, 1.7 Hz,1H), 4.43 (t, J=8.5 Hz, 1H), 4.10 (m, 1H), 3.74 (m, 1H), 3.56 (t, J=8.9Hz, 1H), 3.16 (quint., J=8.9 Hz, 1H), 2.42 (dt, J=12.8, 7.3 Hz, 1H),2.11 (m, 1H), 2.07 (m, 1H), 1.83 (s, 3H), 1.72 (dt, J=12.8, 9.8 Hz, 1H),1.55 (dd, J=6.7, 1.8 Hz, 3H), 1.5-1.35 (m, 2H).

MS: (M+H)⁺=311, (M+Na)⁺=333, (M−H)⁻=309, (M+CF₃COO⁻)⁻=423, (2M−H)⁻=619.

EXAMPLE 94(±)-(2R,3S,5R,1′R,2′S,3′S)-2-(1-Acetamido-2-methoxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

94A(±)-(2R,3S,5R,1′R,2′S,3′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound is prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R,2′S,3′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

94B(±)-(2R,3S,5R,1′R,2′S,3′S)-2-(1-Acetamido-2-methoxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound is prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S,3′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-3-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 95(±)-(2R,3S,5R,1′RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

95A(±)-(2R,3S,5R,1′RS)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42A, substituting(±)-(2R,3S,5R,1′R,2′RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6.8 mg, 88%).

MS: (M+H)⁺=579, (M−H)⁻=577.

95B(±)-(2R,3S,5R,1′RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0037 g, 100%).

MS: (M+H)⁺=423, (M−H)⁻=421.

EXAMPLE 96(±)-(2R,3S,5R,1′RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

96A(±)-(2R,3S,5R,1′RS)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42A, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6.8 mg, 88%).

MS: (M+H)⁺=579, (M−H)⁻=577.

96B(±)-(2R,3S,5R,1′RS)-2-(1-Acetamido-2-oxo-2-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-heptafluoropropyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0037 g, 100%).

MS: (M+H)⁺=423, (M−H)⁻=421.

EXAMPLE 97(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

97A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 42A, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 14 mg, 58%).

MS: (M+H)⁺=453, (M+Na)⁺=475; (M−H)⁻=451.

97B(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 1.4 mg, 28%).

¹H NMR (DMSO-d₆) δ 8.31 (d, J=8.3 Hz, 1H), 5.40 (m, 1H), 5.19 (br t,1H), 4.26 (t, J=6.8 Hz, 1H), 3.63 (t, J=8.3 Hz, 1H), 3.35 (m, 1H), 2.97(m, 1H), 2.45 (m, 1H), 2.34 (dt, J=3.4, 7.4 Hz, 1H), 2.20 (m, 1H), 1.84(s, 3H), 1.58 (dd, J=2, 4.3 Hz, 3H), 1.43 (m, 3H), 0.82 (t, J=7.3 Hz,3H).

MS: (M−H)⁻=295; (M+H)⁺=297, (M+Na)⁺=319.

EXAMPLE 98(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester prepared in Example 42A in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 5.0 mg, 100%).

¹H NMR (DMSO-d₆) δ 8.52 (d, J=8.6 Hz, 1H), 5.47 (m, 1H), 5.15 (m, 1H),4.54 (m, 1H), 4.39 (dd, J=11.0, 6.7 Hz, 1H), 3.84 (t, J=9.2 Hz, 1H),3.17 (m, 1H), 2.50 (m, 1H), 2.38 (m, 1H), 2.33 (m, 1H), 1.83 (s, 3H),1.63 (m, 1H), 1.58 (dd, J=6.7, 1.8 Hz, 3H), 0.94 (t, J=7.5 Hz, 3H).

MS: (M+H)⁺=283, (M+Na)⁺=305, (M−H)⁻=281.

EXAMPLES 99-115

The title compounds were prepared according to the methods described inExamples 20 and 40-42 by substituting the respective reactants.

EXAMPLE 99

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 8.38 (d, J=8.5 Hz, 1H), 5.73 (m, 1H), 5.37 (m, 1H),5.05 (m, 3H), 4.32 (t, J=7.9 Hz, 1H), 3.90 (m, 1H), 3.49 (m, 1H), 3.13(m, 2H), 2.98 (m, 1H), 3.18 (m, 1H), 1.78 (s, 3H), 1.51 (dd, J=5.5, 1.2Hz, 3H), 1.44 (m, 1H).

MS: (M+H)⁺=295, (M−H)−=293.

EXAMPLE 100

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 8.64 (d, J=8.5 Hz, 1H), 5.59 (m, 1H), 5.08 (d, J=17.1Hz, 1H), 5.02 (d, J=9.8 Hz, 1H), 4.65 (t, J=8.6 Hz, 1H), 4.32 (m, 1H),3.82 (t, J=9.2 Hz, 1H), 2.82 (m, 2H), 2.36 (m, 1H), 1.83 (s, 3H), 1.80(m, 1H), 1.03 (d, J=6.7 Hz, 3H), 0.97 (d, J=6.7 Hz, 3H).

MS: (M+H)⁺=283, (M+Na)⁺=305, (M−H)⁻=281.

EXAMPLE 101

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo)propyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 8.96 (d, J=7.9 Hz, 1H), 5.71 (m, 1H), 5.27 (d, J=17.7Hz, 1H), 5.17 (d, J=11.0 Hz, 1H), 4.38 (m, 1H), 4.29 (m, 1H), 3.81 (m,1H), 2.61 (m, 1H), 2.22 (m, 1H), 2.13 (s, 3H), 2.01 (s, 3H), 1.24 (m,1H).

MS: (M+H)⁺=255, (M+Na)⁺=277, (M−H)⁻=253.

EXAMPLE 102

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 8.61 (d, J=8.5 Hz, 1H), 5.60 (m, 1H), 5.10 (d, J=17.7Hz, 1H), 5.03 (dd, J=10.4, 1.2 Hz, 1H), 4.54 (t, J=8.5 Hz, 1H), 4.38(dd, J=11.0, 6.7 Hz, 1H), 3.86 (m, 1H), 2.84 (m, 1H), 2.52 (m, 1H), 2.37(m, 2H), 1.85 (s, 3H), 1.82 (m, 1H), 0.94 (t, J=7.0 Hz, 3H).

MS: (M+H)⁺=269, (M+Na)⁺=291, (M−H)⁻=267.

EXAMPLE 103

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 8.60 (d, J=9.7 Hz, 1H), 5.60 (m, 1H), 5.07 (m, 2H),4.65 (m, 1H), 4.54 (m, 1H), 4.38 (m, 1H), 3.86 (m, 1H), 2.84 (m, 1H),2.45 (m, 1H), 2.36 (m, 1H), 1.86 (s, 3H), 1.82 (m, 1H), 1.47 (m, 2H),0.87 (t, J=5.8 Hz, 3H).

MS: (M+H)⁺=283, (M+Na)⁺=305, (M−H)⁻=281.

EXAMPLE 104

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 8.00 (d, J=9.9 Hz, 1H), 5.63 (m, 1H), 5.08 (m, 1H),4.98 (m, 1H), 4.35 (m, 1H), 4.25 (m, 1H), 4.08 (m, 1H), 3.55 (m, 1H),3.45 (m, 1H), 3.38 (m, 1H), 2.83 (m, 1H), 2.33 (m, 1H), 1.78 (s, 3H).

MS: (M+H)⁺=243, (M+Na)+=265, (M−H)−=241.

EXAMPLE 105

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)propyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.96 (d, J=9.7 Hz, 1H), 5.74 (m, 1H), 5.12 (m, 1H),5.03 (m, 1H), 4.27 (m, 1H), 3.96 (m, 1H), 3.77 (m, 1H), 3.65 (m, 1H),2.87 (m, 1H), 2.38 (m, 1H), 1.82 (s, 3H), 1.80 (m, 1H), 1.08 (d, J=6.0Hz, 3H).

MS: (M+H)⁺=257, (M+Na)⁺=279, (M−H)⁻=255.

EXAMPLE 106

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.99 (d, J=9.0 Hz, 1H), 5.75 (m, 1H), 5.13 (d, J=17.1Hz, 1H), 5.04 (d, J=10.5 Hz, 1H), 4.27 (t, J=8.4 Hz, 1H), 4.04 (m, 1H),3.78 (m, 1H), 3.48 (m, 1H), 2.89 (m, 1H), 2.40 (m, 1H), 1.88 (m, 1H),1.85 (s, 3H), 1.54 (m, 1H), 1.28 (m, 1H), 0.86 (t, J=7.2 Hz, 3H).

MS: (M+H)⁺=271, (M+Na)+=293, (M−H)−=269.

EXAMPLE 107

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.99 (d, J=9.9 Hz, 1H), 5.75 (m, 1H), 5.08 (m, 2H),4.28 (m, 1H), 4.03 (m, 1H), 3.77 (m, 1H), 3.52 (m, 1H), 2.88 (m, 1H),2.40 (m, 1H), 1.86 (s, 3H), 1.75 (m, 1H), 1.45 (m, 2H), 1.25 (m, 2H),0.87 (t, J=5.9 Hz, 3H).

MS: (M+H)⁺=285, (M+Na)⁺=307, (M−H)⁻=283.

EXAMPLE 108

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.97 (d, J=9.3 Hz, 1H), 5.75 (m, 1H), 5.12 (d, J=17.1Hz, 1H), 5.04 (d, J=11.2 Hz, 1H), 4.24 (m, 1H), 4.13 (m, 1H), 3.74 (dd,J=9.8, 6.1 Hz, 1H), 3.44 (dd, J=10.3, 2.0 Hz, 1H), 2.87 (m, 1H), 2.40(m, 1H), 1.84 (m, 1H), 1.83 (s, 3H), 1.75 (m, 1H), 0.89 (d, J=6.8, 3H),0.75 (d, J=6.8 Hz, 3H).

MS: (M+H)⁺=285, (M+Na)⁺=307, (M−H)⁻=283.

EXAMPLE 109

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-cyclopropyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.81 (d, J=10.0 Hz, 1H), 5.73 (m, 1H), 5.05 (m, 2H),4.39 (m, 1H), 4.20 (m, 1H), 3.90 (m, 1H), 3.61 (m, 1H), 3.08 (m, 1H),2.86 (m, 1H), 2.42 (m, 1H), 1.85 (s, 3H), 0.88 (m, 1H), 0.45 (m, 1H),0.35 (m, 2H), 0.11 (m, 1H).

MS: (M+H)⁺=283, (M+Na)⁺=305, (M−H)⁻=281.

EXAMPLE 110

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)propyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.77 (d, J=9.7 Hz, 1H), 5.72 (m, 1H), 5.07 (m, 2H),4.40 (m, 1H), 4.03 (m, 1H), 3.95 (m, 1H), 3.57 (m, 1H), 2.86 (m, 1H),2.43 (m, 1H), 1.88 (m, 1H), 1.84 (s, 3H), 1.04 (d, J=6.0 Hz, 3H).

MS: (M+H)⁺=257, (M+Na)⁺=279, (M−H)⁻=255.

EXAMPLE 111

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.72 (d, J=9.8 Hz, 1H), 5.73 (m, 1H), 5.08 (d, J=17.1Hz, 1H), 5.03 (d, J=10.4 Hz, 1H), 4.41 (m, 1H), 4.13 (m, 1H), 3.68 (m,1H), 3.63 (m, 1H), 2.88 (m, 1H), 2.44 (m, 1H), 1.90 (m, 1H), 1.83 (s,3H), 1.38 (m, 2H), 0.84 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=271, (M+Na)⁺=293, (M−H)⁻=269.

EXAMPLE 112

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.72 (d, J=9.9 Hz, 1H), 5.72 (m, 1H), 5.06 (m, 2H),4.42 (m, 1H), 4.09 (m, 1H), 3.77 (m, 1H), 3.61 (m, 1H), 2.87 (m, 1H),2.43 (m, 1H), 1.90 (m, 1H), 1.83 (s, 3H), 1.37 (m, 2H), 1.27 (m, 2H),0.87 (t, J=5.9 Hz, 3H).

MS: (M+H)⁺=285, (M+Na)⁺=307, (M−H)⁻=283.

EXAMPLE 113

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-methyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.71 (d, J=9.3 Hz, 1H), 5.70 (m, 1H), 5.08 (d, J=17.1Hz, 1H), 5.03 (d, J=10.3 Hz, 1H), 4.42 (m, 1H), 4.25 (m, 1H), 3.61 (m,1H), 3.35 (dd, J=8.3, 2.5 Hz, 1H), 2.90 (m, 1H), 2.44 (m, 1H), 1.92 (m,1H), 1.82 (s, 3H), 1.58 (m, 1H), 0.95 (d, J=6.8 Hz, 3H), 0.79 (d, J=6.4Hz, 3H).

MS: (M+H)⁺=285, (M+Na)⁺=307, (M−H)−=283.

EXAMPLE 114

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-cyclopropyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.94 (d, J=9.6 Hz, 1H), 5.76 (m, 1H), 5.12 (m, 2H),4.40 (m, 1H), 4.21 (m, 1H), 3.90 (m, 1H), 3.53 (m, 1H), 3.13 (m, 1H),2.81 (m, 1H), 2.25 (m, 1H), 1.87 (s, 3H), 0.90 (m, 1H), 0.47 (m, 1H),0.37 (m, 2H), 0.15 (m, 1H).

MS: (M+H)⁺=283, (M+Na)⁺=305, (M−H)⁻=281.

EXAMPLE 115

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-4-methyl)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.71 (d, J=9.7 Hz, 1H), 5.83 (m, 1H), 5.06 (d, J=17.1Hz, 1H), 5.02 (d, J=10.3 Hz, 1H), 4.41 (m, 1H), 4.06 (m, 1H), 3.83 (m,1H), 3.59 (t, J=8.8 Hz, 1H), 2.84 (m, 1H), 2.42 (m, 1H), 1.90 (m, 1H),1.82 (s, 3H), 1.71 (m, 1H), 1.34 (m, 1H), 1.07 (m, 1H), 0.89 (d, J=6.8Hz, 3H), 0.86 (d, J=6.3 Hz, 3H).

MS: (M+H)⁺=299, (M+Na)⁺=321, (M−H)−=297.

EXAMPLE 116(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

116A(±)-(2R,3S,5R,1′R)-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-t-Butoxycarbonyl2-(1-acetamido-2-oxo)propyl-3-vinyl-pyrrolidine-5-carboxylic acidt-butyl ester (11 mg, 0.027 mmol) was reacted with methyl magnesiumbromide (3 M) (0.05 mL, 0.134 mmol) in THF (2 mL) at 25° C. for 2 hours.The reaction was quenched with saturated aqueous ammonium chloride (2mL) and water (2 mL) followed by extraction using dichloromethane (2×5mL). The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 2/1: ethyl acetate/hexane to provide the titlecompound (yield: 1.9 mg, 17%).

MS: (M+H)⁺=427, (M−H)⁻=425.

116B(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl)propyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 1.6 mg, 99%).

¹H NMR (DMSO-d₆) δ 7.70 (d, J=9.9 Hz, 1H), 5.75 (m, 1H), 5.02 (m, 2H),4.37 (m, 1H), 4.15 (m, 1H), 3.61 (m, 1H), 2.78 (m, 1H), 2.41 (m, 1H),1.81 (s, 3H), 1.20 (s, 3H), 1.12 (s, 3H).

MS: (M+H)⁺=271, (M+23)⁺=293, (M−H)⁻=269.

EXAMPLE 117(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-hydroxy-2-ethyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

117A(±)-(2R,3S,5R,1′R)-t-Butoxycarbonyl-2-(1-Acetamido-2-hydroxy-2-ethyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-t-Butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (37 mg, 0.087 mmol) was reacted with ethyl magnesiumbromide (3 M) (0.15 mL, 0.44mmol) in THF (5 mL) at 25° C. for 2 hours.The reaction was quenched with saturated aqueous ammonium chloride 5 mL)and water (5 mL) followed by extraction using dichloromethane (2×10 mL).The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 2/1: ethyl acetate/hexane to provide the tilecompound (yield: 14 mg, 35%).

MS: (M+H)⁺=455, (M−H)⁻=453.

116B(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-hydroxy-2-ethyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-ethyl)butyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 5.8 mg, 98%).

¹H NMR (DMSO-d₆) δ 7.62 (d, J=9.6 HZ, 1H), 5.75 (m, 1H), 5.03 (m, 2H),4.39 (m, 1H), 4.31 (m, 2H), 3.87 (m, 1H), 3.38 (m, 1H), 2.88 (m, 1H),2.40 (m, 1H), 1.83 (s, 3H), 1.55-1.30 (m, 4H), 0.86 (m, 6H).

MS: (M+H)⁺=299, (M−H)⁻=297.

EXAMPLE 118(±)-(2R,3S,5R,1′S)-2-(1-Acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

118A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 20K, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 15.3 mg, 61.4%).

MS: (M+H)⁺=409.

118B(±)-(2R,3S,5R,1′S)-2-(1-Acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 13.1 mg, 100%).

¹H NMR (DMSO-d₆): δ 1.58 (dd, 3H), 1.74 (dt, 1H), 1.88 (s, 3H), 2.41(dt, 1H), 3.17 (m, 1H), 3.56 (dd, 1H), 4.35 (dd, 1H), 4.70 (dd, 1H),5.22-5.30 (m, 3H), 5.51 (m, 1H), 5.82 (m, 1H), 8.15 (d, 1H), 9.18 (br s,2H).

MS: (M+H)⁺=253.

EXAMPLE 119 (±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(cis andtrans)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic AcidTrifluoroacetic Acid Salt

119A (±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-(cis andtrans)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acidt-Butyl Ester

The title compound was prepared according to the method described inExample 20K, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester and ethyltriphenylphosphonium bromide formethyltriphenylphosphonium bromide (yield: 12.4 mg, 48.2%).

MS: (M+H)⁴=423.

119B (±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(cis andtrans)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic AcidTrifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-(cis andtrans)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acidt-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 11.8 mg, 100%).

¹H NMR (DMSO-d₆): δ 1.63 (dd, 3H), 1.66 (dd, 3H), 1.74 (m, 1H), 1.88 (s,3H), 2.41 (dt, 1H), 3.17 (m, 1H), 3.50 (dd, 1H), 4.34 (dd, 1H), 4.95 (m,1H), 5.23 (m, 1H), 5.39 (m, 1H), 5.53 (m, 1H), 5.68 (m, 1H), 8.21 (d,1H), 9.18 (br s, 2H).

MS: (M+H)⁺=267.

EXAMPLE 120(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3,3-dimethyl)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

120A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3,3-dimethyl)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 20K, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester and isopropyltriphenylphosphonium bromide formethyltriphenylphosphonium bromide (yield: 8.2 mg, 25.9%).

MS: (M+H)⁺=437.

120B(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3,3-dimethyl)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3,3-dimethyl)allyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. ester (yield: 7.5 mg, 100%).

¹H NMR (DMSO-d₆): δ 1.53 (dd, 3H), 1.57 (s, 3H), 1.61 (s, 3H), 1.66 (m,1H), 1.77 (s, 3H), 2.32 (dt, 1H), 3.07 (m, 1H), 3.39 (dd, 1H), 4.26 (m,1H), 4.75 (m, 1H), 5.07 (d, 1H), 5.15 (m, 1H), 5.44 (m, 1H), 8.06 (d,1H).

MS: (M+H)⁺=281.

EXAMPLE 121 (±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(cis andtrans)penten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic AcidTrifluoroacetic Acid Salt

121A (±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-(cis andtrans)penten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acidt-Butyl Ester

The title compound was prepared according to the method described inExample substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester and n-butyl-triphenylphosphonium bromide formethyltriphenylphosphonium bromide (yield: 21.0 mg, 66.2%).

MS: (M+H)⁺=437.

121B (±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(cis andtrans)penten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic AcidTrifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-(cis andtrans)penten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic acidt-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. ester (yield: 16.0 mg, 98.1%).

¹H NMR (DMSO-d₆): δ 0.93 (t, 3H), 1.62 (dd, 3H), 1.75 (m, 1H), 1.87 (s,3H), 2.07 (m, 2H), 2.40 (m, 1H), 3.17 (m, 1H), 3.50 (m, 1H), 4.34 (m,1H), 4.94 (m, 1H), 5.23 (m, 1H), 5.34 (m, 1H), 5.53 (m, 1H), 5.58 (m,1H), 8.24 (d, 1H), 9.25 (br s, 2H).

MS: (M+H)⁺=281.

EXAMPLE 122 (±)-(2R,3S,5R,1′S)-2-(1-Acetamido-4-hydroxy-2-(cis andtrans)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic AcidTrifluoroacetic Acid Salt

122A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-4-(t-butyldimethylsilyloxy)-2-(cisand trans)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic Acidt-Butyl Ester

The title compound was prepared according to the method described inExample substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester and4-(t-butyldimethylsilyloxy)butyltriphenylphosphonium bromide formethyltriphenylphosphonium bromide (yield: 23.1 mg, 66.9%).

MS: (M+H)⁺=567.

122B (±)-(2R,3S,5R,1′S)-2-(1-Acetamido-4-hydroxy-2-(cis andtrans)buten-1-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylic AcidTrifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-(cis andtrans)4-hydroxy-butenyl-2-yl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 16.9 mg, >100%).

¹H NMR (DMSO-d₆): δ 1.67 (dd, 3H), 1.78 (dt, 1H), 1.91 (s, 3H), 2.44 (m,1H), 2.50 (m, 1H), 2.56 (m, 1H), 2.65 (m, 1H), 3.23 (m, 1H), 3.54 (m,1H), 4.40 (m, 1H), 4.47 (m, 2H), 5.01 (m, 1H), 5.26 (m, 1H), 5.54 (m,2H), 5.63 (m, 1H), 8.32 (d, 1H), 9.27 (br s, 2H).

MS: (M+H)⁺=297.

EXAMPLE 123(±)-(2R,3S,5R,1′S)-2-(1-Acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride

123A(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (30.8 g, 97.1 mmol) was reacted witht-butyldiphenylsilyl chloride (49.5 mL, 190.4 mmol) and imidazole indichloromethane (650 mL) at 0° C. for 1 hour. The reaction was quenchedmethanol followed by extraction with dichloromethane (600 mL). Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 2/1: chloroform/hexane to provide the title compound(yield: 52.9 g, 98%).

¹H NMR (CDCl₃) 7.62-7.67 (m, 4H), 7.32-7.44 (m, 6H), 7.25-7.30 (m, 5H),5.58-5.72 (m, 1H), 5.06-5.14 (m, 2H), 3.90 (d, 1H), 3.72-3.78 (m, 1H),3.58-3.68 (m, 2H), 3.44-3.52 (m, 2H), 2.26-2.40 (m, 1H), 2.10-2.23 (m,1H), 1.68-1.78 (m, 1H), 1.38 (s, 9H), 1.03 (s, 9H).

MS: (M+H)⁺=556.

123B(±)-(2R,3R,5R,1′RS)-1-Benzyl-2-(1,2-dihydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R)-1-Benzyl-2-vinyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (22.7 g, 41 mmol) was reacted with OsO4 (4%) (2.5 mL,0.7 mol. %) and N-methyl morpholine N-oxide (18.5 g, 2.77 eq.) inacetone (500 mL) and water (60 mL) for 48 h at room temperature. Thereaction was quenched with 10% aqueous Na₂S₂O₃ (200 mL). The reactionwas concentrated in vacuo and the residue was partitioned between ethylacetate/water. The organic layer was dried over magnesium sulfate,filtered and concentrated in vacuo. The residue was purified by columnchromatography on silica gel using 35% ethyl acetate/hexane to providethe title compound (yield: 11 g, 55%).

¹H NMR (DMSO-d₆) δ 7.58-7.63 (m, 5H), 7.40-7.48 (m, 7H), 7.20-7.35 (m,3H), 4.41-4.45 (m, 2H), 3.98 (d, 1H), 3.75-3.84 (m, 2H), 3.50-3.68 (m,2H), 3.4-3.46 (m, 1H), 3.16-3.25 (m, 1H), 2.97-3.0 (m, 1H), 2.09-2.28(m, 1H), 1.62-1.89 (m, 1H), 1.34-1.39 (m, 1H), 1.30 (s, 9H), 98.96 (2s,9H).

MS: (M+H)⁺=590.

123C(±)-(2R,3R,5R,1′RS)-2-(1,2-dihydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′RS)-1-Benzyl-2-(1,2-dihydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (11 g, 18.7 mmol) was reacted under 1 atmosphere ofhydrogen with 20% Pd(OH)₂/C (5 g) and in ethanol (40 mL) vigorouslystirred for 2.5 days at room temperature. The reaction was filtered, andthe catalyst was washed with methanol (3×30 mL). The filtrate wasevaporated in vacuo to give the tide compound as an oil (yield: 8 g,94%).

123D(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1,2-dihydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 40D, substituting(±)-(2R,3R,5R,1′RS)-2-(1,2-dihydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(2R,3R,5R,1′RS)-2-(1,2-dihydroxy)ethyl-3-acetoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester. The residue was purified by column chromatography onsilica gel using 35% ethyl acetate/hexane to provide the title compound(yield: 20.5 g, 60%).

¹H NMR (DMSO-d₆) 7.57-7.60 (m, 4H), 7.38-7.48 (m, 6H), 4.85, 4.77 (2d,1H), 4.45-4.50 (m, 1H), 4.02-4.10 (m, 1H), 3.80-3.95 (m, 1H), 3.73, 3.68(2s, 1H), 3.45-3.67 (m, 2H), 3.18-3.28 (m, 2H), 2.36-2.46 (m, 2H), 1.86,1.70 (2d, 1H), 1.40, 1.35 (2s, 9H), 1.32, 1.26 (2s, 9H), 1.0, 0.98 (2s,9H).

MS: (M+H)⁺=600.

123E(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-methanesulfonyloxy-2-acetoxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1,2-dihydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (20.5 g, 34.2 mmole) was reacted with aceticanhydride (16.1 mL, 171 mmole) and triethylamine (47.7 mL, 342 mmole) indichloromethane (360 mL) at 0° C. for 16 h.

The reaction was treated with methanol (35 mL) for 10 minutes anddiluted with dichloromethane (1300 mL). The organic layer was washedwith water,and brine, dried over MgSO₄, filtered and concentrated invacuo. The residue was reacted with methanesulfonyl chloride (4.0 mL,51.3 mmole) and triethylamine (14.3 mL, 103 mmole) in dichloromethane(350 mL) at 0° C. for 1.5 hours. The reaction was quenched with water(300 mL) and diluted with dichloromethane (1200 mL). The organic layerwas washed with water,and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 30% ethyl acetate/hexanes to provide the title compound(yield: 23.8 g, 97%).

¹H NMR (DMSO-d₆) δ 7.58-7.62 (m, 4H), 7.38-7.50 (m, 6H), 5.12-5.26 (2m,1H), 4.06-4.25 (m, 3H), 4.00 (d, 1H), 3.46-3.68 (m, 2H), 3.20, 3.18 (2s,3H), 2.40-2.48 (m, 1H), 2.02, 1.99(2s, 3H), 1.68-1.88 (m, 1H), 1.42,1.36 (2s, 9H), 1.31, 1.25 (2s, 9H), 1.00, 0.98 (2s, 9H).

MS: (M+H)⁺=720, (M+NH₄)⁺=737,

123F(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-methanesulfonyloxy-2-acetoxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (23.8 g, 33.1 mmole) was reacted with potassiumcarbonate (10.1 g, 66.2 mmole) in methanol (160 mL) and THF (160 mL) at25° C. for 18 hours. The reaction was concentrated in vacuo. The residuewas dissolved in ethyl acetate and washed with water,and brine, driedover MgSO₄, filtered and concentrated in vacuo. The residue was purifiedby chromatography on silica gel using 25% ethyl acetate/hexanes toprovide the title compound, as an oil (yield: 16.7 g, 87%).

¹H NMR (CDCl₃) δ 7.60-7.68 (m, 4H), 7.32-7.45 (m, 6H), 4.02-4.28 (m,2H), 3.67-3.78 (m, 1H), 3.52-3.62 (m, 1H), 3.0-3.08 (m, 1H), 2.68-2.75(m, 1H), 2.47-2.52 (m, 3H), 1.80-1.90 (m, 1H), 1.48, 1.42 (2s, 9H),1.37, 1.35 (2s, 9H), 1.07, 1.03 (2s, 9H).

MS: (M+H)⁺=582.

123G(±)-(2R,3R)-5R,1′S)-1-t-Butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (4.17 g, 7.2 mmole) was reacted withtetrabutylammonium fluoride (1M) (14 mL,14.0 mmole) in THF (7 mL) for 20minutes at 0° C. then for 1.5 hours at 25° C. The reaction wasconcentrated in vacuo the residue was dissolved in ethyl acetate andwashed with pH 7.0 buffer and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 50% ethyl acetate/hexanes to provide the titlecompound, as an oil (yield: 2.4 g, 97%).

¹H NMR (DMSO-d₆) δ 4.72-4.78 (m, 1H), 3.94-4.05 (m, 2H), 3.35-3.47 (m,1H), 3.18-3.28 (m, 1H), 3.03-3.08 (m, 1H), 2.63-2.73 (m, 1H), 2.37-2.44(m, 1H), 2.30-2.36 (m, 1H), 2.08-2.20 (m, 1H), 1.58-1.75 (m, 1H), 1.40(s, 9H), 1.37, 1.34 (2s, 9H).

MS: (M+H)⁺=344, (M+Na)⁺=366.

123H(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-oxiranyl-3-formyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (2.4 g, 7.0 mmole) and triethylamine (3.9 mL 28.0mmole) in dichloromethane (70 mL) at 0° C. was reacted with sulfurtrioxide pyridine complex (3.35 g, 21.0 mmole) in dimethylsulfoxide (21mL) by dropwise addition followed by reaction for an additional 3 hours.The reaction was quenched with water (50 mL) and diluted with ethylacetate (200 mL); The organic layer was washed with water,and brine,dried over MgSO₄, filtered and concentrated in vacuo to provide thetitle compound (yield: 2.2 9,).

¹H NMR (DMSO-d₆) (rotamers) δ 9.58 and 9.56 (2s, 1H), 4.70 and 4.53 (2m,1H), 3.96 (dd, J=1.4, 9.2 Hz, 1H), 3.25-3.20 (m, 1H), 2.91 (m, 1H), 2.71(m, 1H), 2.50-2.28 (m, 3H), 1.42, 1.37, 1.34, and 1.30 (4s, 18H).

MS: (M−H)⁻=340.

123I(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-oxiranyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

Triphenylphosphoranylidenemethyl ylide (17.6 mmole) prepared by reactingmethyltriphenylphosphonium bromide (12.63 g, 35.4 mmole) and potassiumtert-butoxide (1M) (17.6 mL, 17.6 mmole) in THF (70 mL) for 1 hour at25° C.(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-oxiranyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (2.2 g, 6.5 mmole) in THF (10 mL) was added to theabove solution at 0° C. and stirred for 0.5 hours. The reaction wasquenched with saturated ammonium chloride (50 mL) and diluted with ethylacetate (200 mL). The organic layer was washed with water,and brine,dried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel using 10% ethyl acetate/hexanesto provide the title compound (yield: 2 g, 84%).

¹H NMR (DMSO-d₆) δ 5.80-5.95 (m, 1H), 5.08 (d, 1H), 4.94-5.04 (1H),4.00-4.07 (m, 1H), 3.59, 3.90 (2t, 1H), 3.07-3.16 (m, 1H), 2.73-2.81 (m,1H), 2.65-2.72 (m, 1H), 2.35-2.48 (m, 1H), 1.59-1.76 (m, 1H), 1.42 (s,9H), 1.38, 1.35 (2s, 9H).

MS: (M+H)⁺=340.

123J(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-oxiranyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (1.72 g, 5.1 mmole) and ammonium chloride (1.36 g,25.4 mmole) in ethanol (45 mL) and water (5 mL) was reacted with lithiumazide (1.2 g, 24.5 mmole) for 7 hours at 50° C. The reaction wasconcentrated in vacuo and diluted with ethyl acetate (200 mL). Theorganic layer was washed with water,and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue (2.15 g) was dissolvedin dichloromethane (50 mL) and reacted with methanesulfonyl chloride(0.8 mL, 10.2 mmole) and triethylamine (2.8 mL, 20.4 mmole) for 0.5hours at 0° C. The reaction was quenched with aqueous sodium bicarbonate(50 mL) and diluted with ethyl acetate (200 mL). The organic layer waswashed with water,and brine, dried over MgSO₄, filtered and concentratedin vacuo. The residue was purified by chromatography on silica gel using10% ethyl acetate/hexanes to provide the title compound (yield: 1.87 g,80%).

¹H NMR (DMSO-d₆) δ 5.77-5.98 (m, 1H), 4.94-5.11 (m, 3H), 4.12-4.19 (m,1H), 3.99-4.06 (m, 1H), 3.66, 3.71 (2d, 1H), 3.25, 3.22 (2s, 3H),2.92-3.02 (m, 1H), 2.55-2.63 (m, 1H), 1.68-1.82 (m, 1H), 1.45, 1.42 (2s,9H), 1.38, 1.36 (2s, 9H).

MS: (M+H)⁺=461.

123K(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (2.12 g, 4.6 mmole) was reacted withtriphenylphosphine (1.81 g, 6.9 mmole) in THF (30 mL) and water (7.5 mL)at 65° C. for 1 hour. The reaction was concentrated in vacuo andredissolved in ethyl acetate (200 mL). The organic layer was washed withwater,and brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel using 4%methanol in dichloromethane to provide 2 g of the crude title compoundcontaining approximately 60% product and 40% Ph₃PO which was useddirectly for acylation.

¹H NMR (DMSO-d₆) δ 5.78-5.5.98 (m, 1H), 4.12 (d, 1H), 3.42, 3.19 (2d,1H), 2.53-2.73 (m, 2H), 2.00-2.15 (m, 1H), 1.68-1.76 (m, 1H), 1.62-1.68(m, 1H), 1.41 (s, 9H), 1.37, 1.36 (2s, 9H).

MS: (M+H)⁺=339, (M+Na)⁺=361.

123L(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (1.03 g, 3.1 mmole) was reacted with acetic anhydride(0.42 mL, 4.7 mmole) and triethylamine (1.3 mL, 9.3 mmole) indichloromethane (30 mL) at 25° C. for 1 hours. The reaction was quenchedwith water (50 mL) and diluted with ethyl acetate (200 mL). The organiclayer was washed with water,and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 20% ethyl acetate/hexanes to provide the title compound(yield: 75 g, 64%).

¹H NMR (DMSO-d₆) δ 5.78-5.98 (m, 1H), 5.05 (d, 1H), 4.98, 4.94 (2d, 1H),4.12-4.20 (m, 1H), 3.54, 3.42 (2dd, 1H), 2.54-2.98 (m, 3H), 2.40, 2.49(2d, 1H), 2.15, 2.19 (2d, 1H), 2.02, 2.04 (2s, 3H), 1.68-1.82 (m, 1H),1.42 (s, 9H), 1.48, 1.45 (2s, 9H).

MS: (2M+Na)⁺=783.

123M(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

To a suspension of copper(I) bromide-dimethyl sulfide complex (0.051 g,0.248 mmol) in THF (1.0 ml) at 0° C. was added ethylmagnesium bromide(1M) (1.0 ml, 1.0 mmol) in THF. After stirring for 10 minutes at 0° C.,a portion of this solution (0.60 ml) was added dropwise to a solution of(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (0.020 g, 0.053 mmole) in THF (0.40 ml) at −78° C.After stirring for 20 minutes at −78° C., the reaction was warmed to 0°C. and stirred for 30 minutes. The reaction was quenched with saturatedammonium chloride (1.0 mL) and diluted with ethyl acetate (10 mL). Theorganic layer was washed with water and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel using a gradient of 0-75% ethylacetate/hexanes to provide the title compound (yield: 0.004 g, 19%).

¹H NMR (DMSO-d₆) (rotamers) δ 7.48 (d, J=9.5 Hz, 1H), 5.98-5.80 (m, 1H),5.00-4.90 (m, 2H), 4.45-4.25 (m, 1H), 3.96-3.91 (m, 1H), 3.60-3.57 and3.53-3.50 (2m, 1H), 2.91-2.76 (m, 1H), 2.59-2.42 (m, 1H), 1.80 (s, 3H),1.73-1.59 (m, 1H), 1.42 and 1.41 (2s, 9H), 1.40-1.15 (m, 4H), 1.37 and1.34 (2s, 9H), 0.89-0.82 (m, 3H).

MS: (M−H)⁻=409, (M+H)⁺=411.

123N(±)-(2R,3S,5R,1′S)-2-(1-Acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloric Acid Salt

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.1 mg, 99%).

¹H NMR (DMSO-d₆) δ 8.11 (d, J=7.3 Hz, 1H), 5.76-5.69 (m, 1H), 5.16 (d,J=17.1 Hz, 1H), 5.07 (dd, J=1.5, 10.3 Hz, 1H), 4.30 (dd, J=7.3, 9.8 Hz,1H), 4.13 (m, 1H), 3.50 (dd, J=5.9, 9.8 Hz, 1H), 2.90 (m, 1H), 2.39 (m,1H), 1.92-1.85 (m, 1H), 1.87 (s, 3H), 1.52-1.18 (m, 4H), 0.85 (t, J=7.3,3H).

MS: (M−H)⁻=253, (M+H)⁺=255.

EXAMPLES 124-130

The following title compounds were prepared in two steps according tothe methods described in Examples 123M and 123N, the denoted reagentsand their respective methods of preparation are substituted in place ofdiethylcuprate and its preparation in Example 123M for step 1.

EXAMPLE 124

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido)hexyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloric Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 123M, substituting 2Mbutylmagnesium chloride for 1M ethylmagnesium bromide.

¹H NMR (MeOD-d₃) δ 5.82-5.70 (m, 1H), 5.29 (d, J=17.0 Hz, 1H), 5.17 (dd,J=1.3, 10.2 Hz, 1H), 4.35 (dd, J=7.5, 10.2 Hz, 1H), 4.19 (m, 1H), 3.65(dd, J=3.4, 9.8 Hz, 1H), 3.01 (m, 1H), 2.55 (m, 1H), 2.08-1.97 (m, 1H),2.04 (s, 3H), 1.62-1.31 (m, 8H), 0.91 (t, J=6.4 Hz, 3H).

MS: (M−H)⁻=281, (M+H)⁺=283.

EXAMPLE 125

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-4-methyl)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloric Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 123M, substitutingiso-butylmagnesium chloride for ethylmagnesium bromide.

¹H NMR (MeOD-d₃) δ 5.83-5.71 (m, 1H), 5.29 (dd, J=0.7, 17.0 Hz, 1H),5.17 (dd, J=0.7, 10.2 Hz, 1H), 4.34 (dd, J=7.5, 10.2 Hz, 1H), 4.15 (m,1H), 3.66 (dd, J=3.4, 9.8 Hz, 1H), 3.01 (m, 1H), 2.55 (m, 1H), 2.08-1.97(m, 1H), 2.04 (s, 3H), 1.65-1.10 (m, 5H), 0.91 (d, J=6.4 Hz, 3H), 0.91(d, J=6.5 Hz, 3H).

(M+H)⁺=283.

EXAMPLE 126

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3,3-dimethyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloric Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 123M, substituting 1Mtert-butylmagnesium chloride for 1M ethylmagnesium bromide.

¹H NMR (MeOD-d₃) δ 5.84-5.71 (m, 1H), 5.31 (d, J=17.0 Hz, 1H), 5.19 (d,J=10.2 Hz, 1H), 4.39-4.33 (m, 2H), 3.66 (dd, J=3.4, 9.8 Hz, 1H), 3.02(m, 1H), 2.57 (m, 1H), 2.08-1.97 (m, 1H), 2.02 (s, 3H), 1.55 (dd, J=9.5,14.6 Hz, 1H), 1.42 (dd, J=1.4, 14.6 Hz, 1H), 0.95 (s, 9H).

(M+H)⁺=283.

EXAMPLE 127

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-phenyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloric Acid Salt

Lithium diphenylcurpate was prepared according to the method describedby Lipshutz, B. H. in Organometallics in Synthesis; Schlosser, M., Ed.;Wiley and Sons: New York, 1994; p. 292. This cuprate was used accordingto the methods described in Example 123M, substituting lithiumdiphenylcuprate for the Grignard derived diethylcuprate complex.

¹H NMR (MeOD-d₃) δ 7.35-7.21 (m, 5H), 5.87-5.75 (m, 1H), 5.37 (d, J=16.6Hz, 1H), 5.26 (dd, J=1.0, 10.2 Hz, 1H), 4.53 (m, 1H), 4.37 (dd, J=7.5,9.8 Hz, 1H), 3.70 (dd, J=3.7, 9.8 Hz, 1H), 3.11 (m, 1H), 2.97 (dd,J=6.1, 14.2 Hz, 1H), 2.84 (dd, J=9.5, 14.2 Hz, 1H), 2.59 (m, 1H),2.08-1.99 (m, 1H), 1.93 (s, 3H).

(M−H)⁻=301, (M+H)⁺=303.

EXAMPLE 128

(±)-(2R,33S,5R,1′S)-2-(1-Acetamido-4-phenyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloric Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 123M, substituting 1Mphenethylmagnesium chloride for 1M ethylmagnesium bromide.

¹H NMR (MeOD-d₃) δ 7.29-7.13 (m, 5H), 5.77-5.65 (m, 1H), 5.24 (d, J=16.6Hz, 1H), 5.13 (dd, J=1.0, 9.8 Hz, 1H), 4.33 (dd, J=7.5, 10.2 Hz, 1H),4.22 (m, 1H), 3.62 (dd, J=3.4, 9.8 Hz, 1H), 2.98 (m, 1H), 2.63 (m, 2H),2.54 (m, 1H), 2.06-1.95 (m, 1H), 2.03 (s, 3H), 1.79-1.55 (m, 4H).

(M−H)⁻=329, (M+H)⁺=331.

EXAMPLE 129

(±)-(2R)-3S,5R,1′S)-2-(1-Acetamido-3-phenyl)butyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloric Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 123M, substituting 2Mbenzylmagnesium chloride for 1M ethylmagnesium bromide.

¹H NMR (MeOD-d₃) δ 7.30-7.17 (m, 5H), 5.82-5.70 (m, 1H), 5.28 (d, J=17.0Hz, 1H), 5.17 (d, J=11.2 Hz, 1H), 4.33 (dd, J=7.5, 10.2 Hz, 1H), 4.18(m, 1H), 3.64 (dd, J=3.4, 9.8 Hz, 1H), 3.01 (m, 1H), 2.78 (m, 1H),2.66-2.50 (m, 2H), 2.07 (s, 3H), 2.07-1.85 (m, 3H).

(M−H)⁻=315, (M+H)⁺=317.

EXAMPLE 130(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

130A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(N-t-Butoxycarbonylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (0.058 g, 0.17 mmole) was reacted withdi-t-butyldicarbonate (95 mg, 0.44 mmole) and triethylamine (0.12 mL,0.86 mmole) in dichloromethane (2.0 mL) at room temperature for 1 hour.The reaction was quenched with saturated sodium bicarbonate (1.0 mL) anddiluted with ethyl acetate (20 mL). The organic layer was washed withwater,and brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel using agradient of 0-15% ethyl acetate/dichloromethane to provide the titlecompound (yield: 0.060 g, 80%).

¹H NMR (DMSO-d₆) (rotamers) δ 5.97-5.78 (m, 1H), 5.06-4.93 (m, 2H), 4.15(dd, J=2.0, 9.8 Hz, 1H), 3.40-3.28 (m, 1H), 2.94-2.49 (m, 3H), 2.39 and2.33 (2d, J=6.1, 6.4 Hz, 1H), 2.17 and 2.11 (2d, J=3.7, 3.4, 1H),1.81-1.69 (m, 1H), 1.42-1.36 (m, 27H).

MS: (M+Na)⁺=461 (weak).

130B(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

To a suspension of copper(I) bromide-dimethyl sulfide complex (0.026 g,0.127 mmol) in THF (1.0 ml) at 0° C. was added isopropenylmagnesiumbromide (0.5M) (1.0 ml, 0.50 mmol) in THF. After stirring for 10 minutesat 0° C., the mixture was cooled to −78° C. and a solution of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(N-t-butoxycarbonylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (0.030 g, 0.068 mmole) in THF (1.0 ml) was addeddropwise. After stirring for 10 minutes at −78° C., the reaction waswarmed to 0° C. and stirred for 2 hours. The reaction was quenched withsaturated ammonium chloride (1.0 mL) and diluted with ethyl acetate (10mL). The organic layer was washed with water,and brine, dried overMgSO₄, filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel using a gradient of 0-10% ethylacetate/dichloromethane to provide the title compound (yield: 0.026 g,79%).

¹H NMR (DMSO-d₆) (rotamers) δ 6.64 (m, 1H), 5.96-5.76 (m, 1H), 4.98-4.89(m, 2H), 4.76-4.68 (m, 2H), 4.40-4.25 (m, 1H), 3.94 (m, 1H), 3.60-3.53(m, 1H), 3.02-2.86 (m, 1H), 2.62-2.42 (m, 1H), 2.10-1.99 (m, 2H), 1.72and 1.70 (2s, 3H), 1.72-1.55 (m, 1H), 1.44-1.34 (m, 27H).

MS: (M−H)⁻=479, (M+H)⁺=481.

130C(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(-N-t-butoxycarbonylamino-2-propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (0.024 g, 0.050 mmole) was reacted with lithiumhexamethyldisilazide (1 M) (0.60 mL, 0.60 mmole) in THF (2.0 mL) at −25°C. for 1 hour. To the above reaction was then added acetyl chloride(0.085 mL, 1.20 mmole) at −25° C. and the mixture was stirred for 30minutes. The reaction was quenched with saturated sodium bicarbonate(2.0 mL) and stirred for 30 minutes at room temperature. The reactionwas diluted with ethyl acetate (20 mL). The organic layer was washedwith water,and brine, dried over MgSO₄, filtered and concentrated invacuo. The residue was purified by chromatography on silica gel using agradient of 0-15% ethyl acetate/hexanes to provide the title compound(yield: 0.015 g, 58%) along with unreacted starting material.

¹H NMR (DMSO-d₆) (rotamers) δ 6.01-5.84 (m, 1H), 4.99-4.89 (m, 2H),4.76-4.58 (m, 3H), 4.33 and 4.23 (2d, J=7.8, 8.1 Hz, 1H), 4.13-4.04 (m,1H), 2.69 (m, 1H), 2.62-2.42 (m, 1H), 2.29 (br s, 3H), 2.35-2.14 (m,2H), 1.76-1.55 (m, 1H), 1.60 (s, 3H), 1.50-1.35 (m, 27H).

MS: (M+H)⁺=523.

130D(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-propen-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 12 mg, 99%).

¹H NMR (MeOD-d₃) δ 5.83-5.70 (m, 1H), 5.30 (dd, J=0.7, 17.0 Hz, 1H),5.19 (d, J=10.2 Hz, 1H), 4.79 (s, 1H), 4.71 (s, 1H), 4.46 (m, 1H), 4.30(dd, J=7.8, 9.8 Hz, 1H), 3.66 (dd, J=3.7, 9.8 Hz, 1H), 3.03 (m, 1H),2.56 (m, 1H), 2.40-2.19 (m, 2H), 2.08-1.96 (m, 1H), 2.01 (s, 3H), 1.76(s, 3H).

(M−H)⁻=265, (M+H)⁺=267.

EXAMPLES 131-135

The following title compounds were prepared in 4 steps according to themethods described in Example 130 the denoted reagents for step 1 andtheir respective methods of preparation are substituted in place ofisopropenyl cuprate and its preparation in 130B.

EXAMPLE 131

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-1-(cis andtrans)-propen-1-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylic AcidTrifluoroacetic Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 130B, substituting 0.5M1-propenylmagnesium bromide (mixture of cis and trans isomers) for 0.5Misopropenylmagnesium bromide.

¹H NMR (MeOD-d₃) (2:1 trans:cis ratio) δ 5.81-5.54 (m, 2H), 5.43-5.30(m, 1H), 5.33-5.27 (m, 0.33H, cis isomer), 5.31-5.25 (m, 0.66H, transisomer), 5.20-5.15 (m, 1H), 4.26-4.17 (m, 2H), 3.65 (dd, J=3.4, 9.8 Hz,1H), 2.98 (m, 1H), 2.58-2.48 (m, 1H), 2.45-2.19 (m, 2H), 2.08-1.94 (m,1H), 2.02 (s, 3H), 1.68 (m, 2H, trans isomer), 1.63 (m, 1H, cis isomer).

(M−H)⁻=265, (M+H)⁺=267.

EXAMPLE 132

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-allyl)methyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 130B, substituting 1Mvinylmagnesium bromide for 0.5M isopropenylmagnesium bromide.

¹H NMR (MeOD-d₃) δ 5.83-5.70 (m, 2H), 5.28 (d, J=17.0 Hz, 1H), 5.19-5.13(m, 3H), 4.28 (m, 1H), 4.19 (dd, J=8.5, 9.1 Hz, 1H), 3.66 (dd, J=3.4,9.5 Hz, 1H), 2.99 (m, 1H), 2.57-2.48 (m, 1H), 2.44-2.26 (m, 2H),2.05-1.93 (m, 1H), 2.01 (s, 3H).

(M+H)⁺=253.

EXAMPLE 133

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido)-2-(1-buten-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 130B, substituting 0.5M1-buten-2-ylmagnesium bromide for 0.5M isopropenylmagnesium bromide.

¹H NMR (MeOD-d₃) δ 5.81-5.73 (m, 1H), 5.30 (d, J=17.1 Hz, 1H), 5.19 (d,J=10.0 Hz, 1H), 4.93 (s, 1H), 4.83 (s, 1H), 4.45 (m, 1H), 4.31 (dd,J=7.6, 9.8 Hz, 1H), 3.69 (dd, J=3.2, 9.8 Hz, 1H), 3.03 (m, 1H),2.59-2.53 (m, 1H), 2.38 (dd, J=5.9, 14.9 Hz, 1H), 2.30 (dd, J=9.5, 14.9Hz, 1H), 2.07 (q, J=7.6 Hz, 2H), 2.05-1.99 (m, 1H), 2.01 (s, 3H), 1.05(t, J=7.6 Hz, 3H).

(M+H)⁺=281.

EXAMPLE 134

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(trans-2-buten-2-yl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 130B, substituting 0.5M1-methyl-1-propenylmagnesium bromide for 0.5M isopropenylmagnesiumbromide.

¹H NMR (MeOD-d₃) δ 5.83-5.71 (m, 1H), 5.41 (q, J=6.8 Hz, 1H), 5.31 (d,J=17.3 Hz, 1H), 5.19 (d, J=10.2 Hz, 1H), 4.42 (m, 1H), 4.31 (dd, J=7.5,9.8 Hz, 1H), 3.61 (dd, J=4.0, 9.8 Hz, 1H), 3.01 (m, 1H), 2.62-2.52 (m,1H), 2.46 (dd, J=9.5, 13.9 Hz, 1H), 2.26 (dd, J=5.8, 13.9 Hz, 1H),2.09-1.99 (m, 1H), 2.00 (s, 3H), 1.72 (s, 3H), 1.59 (d, J=6.8 Hz, 3H).

(M+H)⁺=281.

EXAMPLE 135(±)-(2R,3S,5R,1′S,3′RS)-2-(1-Acetamido-3-methyl)pentyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The organocuprate reagent was prepared from a Grignard reagent and acatalytic quantity of copper(I) bromide-dimethyl sulfide complexaccording to the methods described in Example 130B, substituting 2Msec-butylmagnesium bromide for 0.5M isopropenylmagnesium bromide.

¹H NMR (MeOD-d₃) (1.1 mixture of methyl isomers) δ 5.82-5.69 (m, 1H),5.27 (d, J=17.0 Hz, 0.5H), 5.25 (d, J=17.0 Hz, 0.5H), 5.15 (d, J=10.2Hz, 1H), 4.33 (m, 1H), 4.18 (dd, J=2.7, 7.5 Hz, 0.5H), 4.15 (dd, J=3.0,7.8 Hz, 0.5H), 3.62 (dd, J=3.1, 9.8 Hz, 0.5H), 3.57 (dd, J=4.07, 9.8 Hz,0.5H), 2.97 (m, 1H), 2.57-2.47 (m, 1H), 2.03-1.92 (m, 1H), 2.03 (s,1.5H), 2.02 (s, 1.5H), 1.72-1.06 (m, 5H), 0.95-0.86 (m, 6H).

(M+H)⁺=283.

EXAMPLE 136(±)-(2R,3S,5R,1′RS)-2-(1-Acetamido-1-(N-methyl-N-benzylcarbamoyl)methyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

136A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-carboxyl)methyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method of Example 2Bsubstituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-1-formyl)methyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester.

136B(±)-(2R,3S,5R,1′RS)-1-t-Butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-benzylcarbamoyl)methyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-carboxyl)methyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (36 mg, 0.09 mmole) was reacted withN-methyl-N-benzylamine (32 mg, 0.26 mmole), dimethylaminopyridine (1 mg,0.008 mmole) and 1-(3-dimethylaminopropyl)-3-ethylcarbodiimidehydrochloride (30 mg, 0.16 mmole) in DMF (3 mL) at 25° C. for 16 hours.The reaction was quenched with water (3 mL) and diluted with ethylacetate (20 mL). The organic layer was washed with water, and brine,dried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel using 50% ethyl acetate/hexanesto provide the title compound.

MS: (M+H)⁺=516, (M−H)⁻=514.

136C(±)-(2R,3S,5R,1′RS)-2-(1-Acetamido-1-(N-methyl-N-benzylcarbamoyl)methyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-benzylcarbamoyl)methyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 7 mg, 95%).

¹H NMR (DMSO₆) δ 8.52 (d, J=9.7 HZ, 1H), 7.30 (m, 5H), 5.65 (m, 1H),5.12 (m, 4H), 4.62 (m, 1H), 4.40 (m, 2H), 3.70 (m, 1H), 2.90 (s, 3H),2.20 (m, 2H), 1.96 (s, 3H).

MS: (M+H)⁺=360, (M+23)⁺=382.

EXAMPLE 138(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-(N-phenyl-carbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

138A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-N-phenyl-carbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (18 mg, 0.045 mmole) was reacted withphenylisocyanate (16 mg, 0.14 mmole) and pyridine (0.1 ml) in THF (3 mL)at 25° C. for 16 hours. The reaction was quenched with water (2 mL) anddiluted with ethyl acetate (10 mL). The organic layer was washed withwater, and brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel using 50% ethylacetate/hexanes to provide the title compound (yield: 7.5 mg, 33%).

MS: (M+H)⁺=518, (M−H)⁻=516.

138B(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-1-(N-phenylcarbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-N-phenyl-carbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4 mg, 95%).

¹H NMR (DMSO-d₆) d 8.36 (d, J=9.7 HZ, 1H), 7.30 (m, 5H), 5.78 (m, 1H),5.22 (m, 1H), 5.10 (m, 1H), 4.58 (m, 1H), 4.45 (m, 1H), 4.14 (, 2H),3.58 (m, 1H), 2.88 (m, 1H), 2.27 (m, 1H), 2.12 (m, 1H), 1.88 (s, 3H).

MS: (M+H)⁺=362, (M+23)⁺=384, (M−H)⁻=360, (M+35)⁻=396.

EXAMPLE 139(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-1-isobutyryloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

139A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-isobutyryloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (15 mg, 0.04 mmole) was reacted with isobutyrylchloride (8 mg, 0.08 mmole) and triethylamine (8 mg, 0.08 mmole) indichloromethane (4 mL) at 0° C. for 2 hours. The reaction was quenchedwith water (3 mL) and diluted with ethyl acetate (20 mL). The organiclayer was washed with water, and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 30% ethyl acetate/hexanes to provide the title compound(yield: 11 mg, 63%).

MS: (M+H)⁺=469, (M−H)⁻=467.

139B(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-1-isobutyryloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-isobutyryloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6.0 mg, 96%).

¹H NMR (DMSO-d₆) δ 8.00 (d, J=9.9 HZ, 1H), 5.63 (m, 1H), 5.08 (m, 1H),4.98 (m, 1H), 4.35 (m, 1H), 4.25 (m, 1H), 4.08 (m, 1H), 3.55 (m, 1H),3.45 (m, 1H), 3.38 (m, 1H), 2.83 (m, 1H), 2.33 (m, 1H), 1.78 (s, 3H).

MS: (M+H)⁺=243, (M+23)⁺=265, (M−H)⁻=241.

EXAMPLE 140(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

140A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (17 mg, 0.04 mmole) was reacted withethylisothiocyanate (19 mg, 0.21 mmole) in pyridine (2 mL) at 70° C. for17 hours. The reaction was quenched with water (3 mL) and diluted withethyl acetate (20 mL). The organic layer was washed with water, andbrine, dried over MgSO₄, filtered and concentrated in vacuo. The residuewas purified by chromatography on silica gel using 70% ethylacetate/hexanes to provide the title compound (yield: 10 mg, 48%).

MS: (M+H)⁺=486, (M+23)⁺=508, (M−H)⁻=485.

140B (±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-N-ethyl-thiocarbonyloxyethyl-3-vinyl-pyrrolidine-5-carboxylic Acid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-N-ethyl-thiocarbonyloxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 7 mg, 94%).

¹H NMR (DMSO-d₆) δ0 8.30 (d, J=9.7 HZ, 1H), 5.78 (m, 1H), 5.25 (m, 1H),5.12 (m, 1H), 4.50 (m, 1H), 4.33 (m, 1H), 4.18 (m, 2H), 3.72 (m, 1H),3.55 (m, 2H), 2.30 (m, 1H), 2.10 (m, 1H), 1.82 (s, 3H), 1.17 (m, 3H).

MS: (M+H)⁺=330, (M−H)⁻=328.

EXAMPLE 141(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-amino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

141A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-t-butoxycarbonylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (9.5 mg, 0.022 mmole) was reacted withtriphenylphosphine (23.5 mg, 0.090 mmole) in ethanol (180 μL) and water(45 μL) at 70° C. for 30 minutes. The reaction mixture was concentratedin vacuo. The residue was dissolved in dichloromethane (220 μL) and toit was added di-tert-butyl dicarbonate (7.3 mg, 0.034 mmol) andN,N-diisopropylethylamine (11.7 mL, 0.067 mmol) at 25° C. After 1 hourthe reaction mixture was diluted with water and extracted with ethylacetate. The organic layers were combined, washed with brine, dried overMgSO₄, and concentrated in vacuo. The residue was purified bychromatography on silica gel using 100% dichloromethane to 50%dichloromethane/ethyl acetate to provide the title compound (yield: 7.5mg, 67%).

¹H NMR (DMSO-d₆) (rotamers) δ 7.51 (d, J=10.5 Hz, 1H), 6.80-6.66 (m,1H), 5.90-5.76 (m, 1H), 5.02-4.90 (m, 2H), 4.38-4.19 (m, 1H), 3.98-3.94(m, 1H), 3.68-3.62 (m, 1H), 3.09-2.73 (m, 2H), 2.60-2.42 (m, 1H), 1.80(s, 3H), 1.72-1.62 (m, 1H), 1.42-1.34 (m, 27H).

MS: (M+H)⁺=498, (M+Na)⁺=520, (M−H)⁻=496, (M+Cl)⁺=532.

141B(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-amino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid DiHydrochloride

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-t-butoxycarbonylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.65 mg, 99%).

¹H NMR (DMSO-d₆) δ 8.24 (d, J=7.9 Hz, 1H), 5.75-5.68 (m, 1H), 5.16 (d,J=17.1 Hz, 1H), 5.06 (d, J=10.4 Hz, 1H), 4.37-4.27 (m, 2H), 3.60-3.16(m, 2H), 3.00-2.88 (m, 2H), 2.46-2.36 (m, 1H), 1.91-1.81 (m, 1H), 1.86(s, 3H).

MS: (M+H)⁺=242, (M+Na)⁺=264, (M−H)⁻=240, (2M−H)⁻=481.

EXAMPLE 142(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-acetamido)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride

142A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-acetamido)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-amino)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (9.4 mg, 0.024 mmole) was reacted with aceticanhydride (11.2 μL) and triethylamine (33.1 μL) in dichloromethane (0.23mL) at 0° C. for 1 hour. The reaction was diluted with water (3 mL),extracted with ethyl acetate (12 mL), washed with brine, dried overMgSO₄, and concentrated in vacuo. The residue was purified bychromatography on silica gel using 100% ethyl acetate to 90% ethylacetate/methanol to provide the title compound (yield: 6.8 mg, 66%).

¹H NMR (DMSO-d₆) (rotamers) δ 7.79-7.74 (m, 1H), 7.54 (d, J=9.8 Hz, 1H),5.97-5.81 (m, 1H), 5.01-4.91 (m, 2H), 4.36-4.27 (m, 1H), 3.97-3.90 (m,1H), 3.68-3.63 (m, 1H), 3.21-3.15 (m, 1H), 3.10-2.76 (m, 1H), 2.88-2.78(m, 1H), 2.58-2.45 (m, 1H), 1.81 (s, 3H), 1.78 (s, 3H), 1.76-1.64 (m,1H), 1.42-1.36 (m, 18H).

MS: (M+H)⁺=439, (M+Na)⁺=462, (M−H)⁻=438, (M+35)⁻=474.

142B(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-acetamido)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′S)-2-(1,2-di-acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylicacid Hydrochloride salt in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.30 mg, 80%).

MS: (M+H)⁺=284, (M−H)⁻=282, (M+Cl)⁻=318.

EXAMPLE 143(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride

143A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-N-acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-6-carboxylicacid t-butyl ester (21.6 mg, 0.064 mmole) was reacted with sodium azide(41.6 mg, 0.64 mmole) and ammonium chloride (34.2 mg, 0.64 mmol) inethanol (270 μL) and water (30 μL) at 75° C. for 1 hour. The ethanol wasthen removed in vacuo and the remaining aqueous was extracted with ethylacetate. The combined organics were washed with brine, dried over MgSO₄,and concentrated in vacuo (crude yield: 20 mg, 82%). To the crudemixture was added acetic anhydride (31 μL, 0.33 mmol) and triethylamine(92 μL, 0.66 mmol) in dichloromethane (330 μL) at 0° C. for 30 minutes.The reaction mixture was then concentrated in vacuo. The residue waspurified by chromatography on silica gel using 100% dichloromethane to50% dichloromethane/ethyl acetate to provide the title compound (yield:10 mg, 60%).

¹H NMR (DMSO-d₆)(rotamers) δ 7.85 and 7.81 (d, J=9.5 Hz and 9.8 Hz, 1H),5.94-5.80 (m, 1H), 5.04-4.93 (m, 2H), 4.58-4.38 (m, 1H), 4.04-3.96 (m,1H), 3.72-3.66 (m, 1H), 3.41-3.21 (m, 2H), 3.09-2.79 (m, 1H), 2.59-2.46(m, 1H), 1.84-1.82 (m, 3H), 1.79-1.53 (m, 1H), 1.43-1.35 (m, 18H).

MS: (M+H)⁺=424, (M+Na)⁺=446, (2M+Na)⁺=869, (M−H)⁻=422, (M+Cl)⁻=458.

143B(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloric Salt.

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2.94 mg, 93%).

¹H NMR (DMSO-d₆) δ 8.24 (d, J=8.55 Hz, 1H), 5.74-5.67 (m, 1H), 5.14 (d,J=17.1 Hz, 1H), 5.06 (d, J=10.4 Hz, 1H), 4.41-4.35 (m, 2H), 3.57-3.36(m, 3H), 2.93-2.90 (m, 1H), 2.44-2.38 (m, 1H), 1.96-1.84 (m, 1H), 1.84(s, 3H).

MS: (M+H)⁺=268, (M−H)⁻=266, (M+Cl)⁻=302.

EXAMPLE 144(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride

144A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-N-acetamido-2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

Methylamine (0.016 g, 0.53 mmole) was reacted withN,O-bis-trimethylsilylacetamide (0.079 g, 0.39 mmole) in DMSO (0.8 mL)at 0° C. for 1 hour.(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(N-acetylaziridinyl)-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (0.040 g, 0.11 mmole) was then reacted with the abovereagent N-trimethylsilylmethylamine at 75° C. for 18 hours. The reactionwas diluted with ethyl acetate (7 mL) washed with water and brine, driedover magnesium sulfate, filtered and concentrated in vacuo. The residuewas purified by chromatography on silica gel usingchloroform-methanol-ammonia to provide the title compound (yield: 0.011g, 25%).

¹H NMR (CDCl₃) δ 5.78-5.98 (m, 1H), 5.90-5.04 (2m, 2H), 4.40-4.55 (brm,1H), 3.90-4.02 (m, 1H), 3.54-3.75 (2m, 1H), 2.25-2.40 (brm, 3H), 2.83,2.85 (2d, 3H), 1.42, 1.44 (2s, 9H), 1.34, 1.37 (2s, 9H).

MS: (M+H)⁺=412.

144B(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 7.2 mg, 99%).

¹H NMR (DMSO-d₆) δ 8.25 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.50 (m,1H), 4.40 (m, 1H), 2.55 (s, 3H), 1.85 (s, 3H).

MS: (M+H)⁺=256.

EXAMPLES 145-164

The following title compounds were prepared according to the methodsdescribed in Examples 141-144 where R′ is equal to hydrogen. Where R orR′ are not equal to hydrogen the corresponding amine is used directlywithout the intermediacy of trimethylsilylation.

EXAMPLE 145

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-N-isopropylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.30 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.40 (br,2H), 3.52-3.68 (br, 1H), 3.10-3.20 (br, 1H), 2.82-2.97 (br, 1H),2.37-2.47 (br, 1H), 1.88 (s, 3H), 1.25 (d, 6H).

MS: (M+H)⁺=284.

EXAMPLE 146

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-N-butylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.25 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.50 (m,1H), 4.38 (m, 1H), 3.60 (m, 1H), 2.90 (m, 3H), 2.40 (m, 2H), 1.87 (s,3H), 1.62 (m, 2H), 1.33 (m, 2H), 0.90 (t, 3H).

MS: (M+H)⁺=298.

EXAMPLE 147

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-N-benzylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (DMSO-d₆) δ 7.56-7.43 (m, 5H), 5.74-5.67 (m, 1H), 5.15-4.99 (m,2H), 4.56 (m, 1H), 4.27-3.93 (m, 3H), 3.66-3.15 (m, 3H), 2.91-2.88 (m,1H), 2.64-2.34 (m, 2H), 1.86 (s, 3H).

MS: (M+H)⁺=332, (M+Na)⁺=354, (M−H)⁻=330, (2M−H)⁻=661.

EXAMPLE 148

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-N-phenethylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.25 (d, 1H), 7.30 (m, 5H), 5.70 (m, 1H), 5.10 (m,2H), 4.50 (br, 1H), 4.35 (br, 1H), 3.61 (m, 1H), 3.17 (m, 3H), 2.98 (m,3H), 2.42 (m, 1H), 1.88 (s, 3H).

MS: (M+H)⁺=346.

EXAMPLE 149

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-N,N-dimethylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.34 (d, J=9.2 Hz, 1H), 5.74-5.67 (m, 1H), 5.12 (d,J=17.1 Hz, 1H), 5.04 (d, J=10.4 Hz, 1H), 4.67-4.62 (m, 1H), 4.40 (dd,J=7.3, 10.4 Hz, 1H), 3.60-3.11 (m, 3H), 2.96-2.83 (m, 1H), 2.50 (s, 6H),2.44-2.38 (m, 1H), 1.92-1.84 (m, 1H), 1.84 (s, 3H).

MS: (M+H)⁺=270, (M+Na)⁺=292, (M−H)⁻=268.

EXAMPLE 150

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-N,N-diethylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.23 (d, 1H), 5.70 (m, 1H), 5.10 (m, 2H), 4.60 (br,1H), 4.40 (br, 1H), 3.12 (m, 4H), 2.88 (m, 1H), 2.42 (m, 1H), 1.85 (s,3H), 1.22 (t, 3H).

MS: (M+H)⁺=298.

EXAMPLE 151

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-N,N-dibutylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.24 (d, 1H), 5.70 (m, 1H), 5.08 (m, 2H), 4.48-4.62(br, 1H), 4.28-4.43 (1H), 3.05 (m, 4H), 2.77-2.92 (br, 1H), 2.34-2.46(br, 2H), 1.84 (s, 3H), 1.64 (m, 4H), 1.30 (m, 4H), 0.93 (t, 6H).

MS: (M+H)⁺=354.

EXAMPLE 152

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-2-hydroxyethylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.20 (d, 1H), 5.70 (m, 1H), 5.15 (d, 1H), 5.08 (d,1H), 4.50 (brm, 1H), 4.38 (brm, 1H), 3.68 (m, 1H), 3.0 (brm, 2H), 2.90(m, 1H), 2.41 (m, 1H), 1.85 (s, 3H).

MS: (M+H)⁺=286.

EXAMPLE 153

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-2-hydroxyethyl-N-ethylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 5.81-5.74 (m, 1H), 5.38 (d, J=17.1 Hz, 1H), 5.22 (d,J=10.0 Hz, 1H), 4.92-4.88 (m, 1H), 4.48 (dd, J=7.6, 9.8 Hz, 1H), 3.91(t, J=4.9 Hz, 2H), 3.85 (dd, J=5.6, 10.0 Hz, 1H), 3.63-3.53 (m, 2H),3.46-3.39 (m, 4H), 3.16-3.13 (m, 1H), 2.66-2.61 (m, 1H), 2.08 (s, 3H),2.06-2.01 (m, 1H), 1.38 (t, J=7.33, 3H).

MS: (M+H)⁺=314, (M+Na)⁺=336, (M−H)⁻=312, (M+Cl)⁻=348, (2M−H)⁻=625.

EXAMPLE 154

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-2-hydroxymethyl-N-propylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.36 (d, J=8.5 Hz, 1H), 5.75-5.68 (m, 1H), 5.13 (d,J=17.1 Hz, 1H), 5.04 (d, J=10.4 Hz, 1H), 4.62 (m, 1H), 4.36 (m, 1H),3.77 (t, J=4.9 Hz, 2H), 3.63-3.59 (m, 1H), 3.50-3.23 (m, 3H), 3.22-3.19(m, 2H), 3.08 (t, J=7.3 Hz, 2H), 2.91-2.87 (m, 1H), 2.44-2.39 (m, 1H),1.99-1.88 (m, 1H), 1.84 (s, 3H), 1.75-1.70 (m, 2H), 0.90 (t, J=6.7 Hz,3H).

MS: (M+H)⁺=328, (M+Na)⁺=350, (M−H)⁻=326, (M+Cl)⁻=362, (2M−H)⁻=653.

EXAMPLE 155

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(imidazol-1-yl))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid DiHydrochloride

¹H NMR (MeOD-d₃) δ 9.06 (s, 1H), 7.72 (s, 1H), 7.58 (s, 1H), 5.84-5.76(m, 1H), 5.39 (d, J=17.1 Hz, 1H), 5.23 (d, J=10.25 Hz, 1H), 4.70-4.66(m, 1H), 4.52-400 4.43 (m, 2H), 3.92-3.89 (m, 1H), 3.20-3.17 (m, 1H),2.67-2.62 (m, 1H), 2.11-2.04 (m, 1H), 1.95-1.89 (m, 1H), 1.91 (s, 3H).

MS: (M+H)⁺=293, (M−H)⁻=291, (M+35)⁺=327.

EXAMPLE 156

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N,N-di-(2-hydroxyethylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

MS: (M+H)⁺=330, (M+Na)⁺=352, (M−H)⁻=328, (M+Cl)⁻=364.

EXAMPLE 157

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-acetyl-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.01, 7.95 (2d, 1H), 5.68-5.80 (m, 1H), 5.02-5.22 (m,2H), 4.30-4.45 (brm, 2H), 3.26, 3.21 (2d, 1H), 2.82-2.95 (brm, 1H),2.38-2.48 (m, 1H), 1.98, 2.02 (2s, 3H), 1.79, 1.82 (2s, 3H).

MS: (M+H)⁺=298.

EXAMPLE 158

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-2-hydroxyethyl-N-methylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.35 (d, J=9.15 Hz, 1H), 5.74-5.67 (m, 1H), 5.12 (d,J=17.1 Hz, 1H), 5.04 (d, J=10.4 Hz, 1H), 4.70 (m, 1H), 4.39 (dd, J=7.3,10.4 Hz, 1H), 3.80-3.75 (m, 3H), 3.61-3.43 (m, 3H), 3.23-3.16 (m, 2H),2.91-2.82 (m, 1H), 2.82 (s, 3H), 2.44-2.39 (m, 1H), 1.92-1.84 (m, 1H),1.84 (s, 3H).

MS: (M+H)⁺=300, (M+Na)⁺=322, (2M+H—H₂O)⁺=581.

EXAMPLE 159

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-propyl-N-methylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) (broad) δ 8.3 (1H), 5.7 (1H), 5.12-5.04 (2H), 4.6 (1H),4.35 (1H), 2.61-2.35 (11H), 1.9 (3H), 1.78-1.63 (2H), 1.9 (3H).

MS: (M+H)⁺=298, (M+Na)⁺=320, (M−H)⁻=296, (M+Cl)⁻=332, (2M−H)⁻=593.

EXAMPLE 160

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-cyclohexyl-N-methylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.26 (m, 1H), 5.75-5.65 (m, 1H), 5.08 (d, J=17.1 Hz,1H), 5.02 (d, J=10.3 Hz, 1H), 4.62 (m, 1H), 4.43-4.40 (m, 1H), 3.62-3.58(m, 1H), 3.46-3.16 (m, 2H), 2.89-2.84 (m, 1H), 2.72 (s, 3H), 2.44-2.39(m, 1H), 2.07-1.80 (m, 5H), 1.81 (s, 3H), 1.63 (m, 1H), 1.45-1.06 (m,6H).

MS: (M+H)⁺=338, (M+Na)⁺=360, (M−H)⁻=336, (M+C1)⁻=372.

EXAMPLE 161

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-benzyl-N-methylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.36 (m, 1H), 7.61-7.46 (m, 5H), 5.69-5.64 (m, 1H),5.07 (d, J=17.1 Hz, 1H), 4.99 (d, J=10.1 Hz, 1H), 4.77 (m, 1H),4.44-4.39 (m, 2H), 4.25 (d, J=12.9, 1H), 3.61 (m, 1H), 3.43 (m, 1H),3.22 (m, 1H), 2.93-2.85 (m, 1H), 2.73 (s, 3H), 2.442.38 (m, 1H),1.92-1.85 (m, 1H), 1.85 (s, 3H).

MS: (M+H)⁺=346

EXAMPLE 162

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-phenethyl-N-methylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.34 (d, J=8.55 Hz, 1H), 7.37-7.26 (m, 5H), 5.76-5.69(m, 1H), 5.14 (d, J=17.1 Hz, 1H), 5.06 (d, J=10.4 Hz, 1H), 4.72 (m, 1H),4.46-4.42 (m, 1H), 3.83-3.20 (m, 6H), 3.13-2.99 (m, 2H), 2.86 (s, 3H),2.95-2.83 (m, 1H), 2.46-2.40 (m, 1H), 1.95-1.81 (m, 1H), 1.86 (s, 3H).

MS: (M+H)⁺=360.

EXAMPLE 163

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-naphthylmethyl-N-methylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹H NMR (DMSO₈) δ 8.41 (d, J=7.3 Hz, 1H), 8.32-7.59 (m, 7H), 5.60 (m,1H), 5.04 (d, J=17.1 Hz, 1H), 4.91 (d, J=9.8 Hz, 1H), 4.97-4.73 (m, 3H),4.39 (m, 1H), 3.70-3.13 (m, 3H), 2.90 (m, 1H), 2.72 (s, 3H), 2.43-2.41(m, 1H), 2.01-1.74 (m, 1H), 1.87 (s, 3H).

MS: (M+H)⁺=395, (M+Na)⁺=418, (M−H)⁻=394, (M+Cl)⁻=430, (2M−H)⁻=789.

EXAMPLE 164

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-morpholinyl))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride Salt

¹NMR (DMSO-d₆) δ 8.28 (d, 1H), 5.75-5.78 (m, 1H), 5.15 (d, 1H), 5.05 (d,1H), 4.65 (brm, 1H), 4.42 (m, 1H), 3.72-3.98 (brm, 3H), 3.62 (m, 1H),2.90 (m, 1H), 2.38-2.48 (m, 1H), 1.85 (s, 3H).

MS: (M+H)⁺=312.

EXAMPLE 165(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

165A (±)-2R,3S,5R,1′S,3′R) and(±)-(2R,3S5R,1′S,3′S)-t-Butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-t-butylamino-N-oxide))ethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-t-butylamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (37 mg, 0.08 mmole) was reacted with them-chloroperoxybenzoic acid (20 mg, 0.08 mmole) in CH₂Cl₂ (0.9 mL) at 0°C. for 1 hour. The reaction was chromatographed directly on silica geleluting with a gradient of acetone to acetone/30% MeOH to provide thetitle compounds isomer (±)-(2R,3S,5R,1′S,3′R) (yield: 0.010 g, 27%) andisomer (±)-(2R,3S,5R,1′S,3′S) (yield: 0.011 g, 29%).

165B(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

The title compound was prepared according to the method described inExample 15C substituting(±)-(2R,3S,5R,1′S,3′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-t-butylamino-N-oxide))ethyl-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 6 mg, 80%).

¹H NMR (CD₃OD) δ 5.72-5.87 (m, 1H), 5.40 (d, 1H), 5.20-5.28 (m, 2H),4.44-4.53 (dd, 1H), 3.73-3.95 (m, 3H), 3.57 (s, 3H), 3.08-3.19 (m, 1H),2.59-2.72 (m, 1H), 2.05-2.15 (m, 1H), 2.04 (s, 3H), 1.54 (s, 9H).

MS: (M+H)⁺=328.

EXAMPLES 166-178

The following title compounds were prepared according to the methoddescribed in Example 165.

EXAMPLE 166

(±)-(2R,3S,5S,1′S,3′R)-2-(1-Acetamido-2-(N-methyl-N-isopropylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.87-5.74 (m, 1H), 5.465.40 (m, 1H), 5.27-5.23 (m,1H), 5.21-5.18 (m, 1H), 4.50 (dd, J=8.1, 9.8 Hz, 1H), 4.04-3.87 (m, 4H),3.54 (s, 3H), 3.20-3.14 (m, 1H), 2.69-2.60 (m, 1H), 2.12-2.01 (m, 1H),2.05 (s, 3H), 1.50 (d, J=6.4 Hz, 3H), 1.48 (d, J=6.4 Hz, 3H).

MS: (M+H)⁺=314, (M+Na)⁺=336, (2M+1)⁺=627, (2M+Na)⁺=649.

EXAMPLE 167

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-methyl-N-propylamino-N-oxideethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.87-5.74 (m, 1H), 5.46-5.40 (m, 1H), 5.27-5.23 (m,1H), 5.21-5.18 (m, 1H), 4.50 (dd, J=8.1, 9.8 Hz, 1H), 4.04-3.87 (m, 4H),3.54 (s, 3H), 3.20-3.14 (m, 1H), 2.69-2.60 (m, 1H), 2.12-2.01 (m, 1H),2.05 (s, 3H), 1.50 (d, J=6.4 Hz, 3H), 1.48 (d, J=6.4 Hz, 3H).

MS: (M+H)⁺=314, (M+H—H₂O)⁻=295.

EXAMPLE 168

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-methyl-N-ethylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.82-5.75 (m, 1H), 5.44 (d, J=17.1 Hz, 1H), 5.26 (d,J=10.4 Hz, 1H), 5.14-5.11 (m, 1H), 4.48-4.45 (m, 1H), 4.9 (d, J=4.9 Hz,2H), 3.87 (dd, J=4.9, 10.4 Hz, 1H), 3.76 (q, J=6.7 Hz, 2H), 3.54 (s,3H), 3.17-3.09 (m, 1H), 2.68-2.62 (m, 1H), 2.06 (s, 3H), 2.09-2.03 (m,1H), 1.45 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=300, (M+Na)⁺=322, (M+H—H₂O)⁺=282.

EXAMPLE 169

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N,N-dimethylamino-N-oxide)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.58 (d, 1H), 5.67-5.78 (m, 1H), 5.20 (d, 1H), 5.08(d, 1H), 4.62-4.78 (brm, 1H), 4.25-4.42 (brm, 1H), 4.06 (d, 1H),3.85-3.95 (brm, 1H), 3.88-3.98 (brm, 1H), 3.35-3.50 (br s, 6H),2.36-2.48 (m, 1H), 1.92 (m, 1H), 1.85 (s, 3H).

MS: (M+H)⁺=286.

EXAMPLE 170

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-methyl-N-benzylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 7.60-7.47 (m, 5H), 5.75-5.65 (m, 1H), 5.39 (d, J=6.35Hz, 1H), 5.21 (d, J=8.8 Hz, 1H), 5.18-5.11 (m, 1H), 5.00-4.70 (m, 2H),4.35-4.27 (m, 1H), 4.00-3.94 (m, 2H), 3.86-3.79 (m, 1H), 3.20 (s, 3H),3.14-3.05 (m, 1H), 2.77-2.50 (m, 1H), 2.08 (s, 3H), 2.10-2.94 (m, 1H).

MS: (M+H)⁺=362, (M+Na)⁺=385, (M−H)⁻=360, (M+35)⁺=396.

EXAMPLE 171

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-methyl-N-t-butylamino-N-oxide)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (CD₃OD) δ 5.80 (m, 1H), 5.44 (d, 1H), 5.27 (d, 1H), 5.08 (m, 1H),4.34-4.44 (dd, 1H), 3.83-3.94 (m, 3H), 3.38 (s, 3H), 3.02-3.18 (m, 1H),2.58-2.72 (m, 1H), 2.08 (s, 3H), 1.97-2.08 (m, 1H), 1.55 (s, 9H).

MS: (M+H)⁺=328.

EXAMPLE 172

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-methyl-N-isopropylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.86-5.74 (m, 1H), 5.53-5.47 (m, 1H), 5.29-5.25 (m,1H), 5.22-5.19 (m, 1H), 4.50 (dd, J=8.1, 9.5 Hz, 1H), 4.13-4.04 (m, 2H),3.96 (dd, J=4.1, 10.5 Hz, 1H), 3.87-3.82 (m, 1H), 3.39 (s, 3H),3.23-3.17 (m, 1H), 2.70-2.61 (m, 1H), 2.11 (s, 3H), 2.08-2.00 (m, 1H),1.50 (d, J=6.4 Hz, 3H), 1.49 (d, J=6.4 Hz, 3H).

MS: (M+H)⁺=314, (M+Na)⁺=336, (2M+1)⁺=627, (2M+Na)⁺=649.

EXAMPLE 173

(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-2-(N-methyl-N-propylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.82-5.75 (m, 1H), 5.45 (d, J=17.1 Hz, 1H), 5.26 (d,J=10.4 Hz, 1H), 5.07-5.13 (m, 1H), 4.48-4.42 (m, 1H), 3.98 (d, J=5.5 Hz,2H), 3.86 (dd, J=4.3, 9.8 Hz, 1H), 3.67-3.64 (m, 2H), 3.46 (s, 3H),3.16-3.01 (m, 1H), 2.68-2.62 (m, 1H), 2.09-2.02 (m, 1H), 2.06 (s, 3H),1.92-1.86 (m, 2H), 1.04 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=314, (M+H—H₂O)⁺=295.

EXAMPLE 174

(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-2-(N-methyl-N-ethylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.82-5.75 (m, 1H), 5.45 (d, J=17.1 Hz, 1H), 5.26 (d,J=10.4 Hz, 1H), 5.13-5.10 (m, 1H), 4.48-4.44 (m, 1H), 4.02-3.94 (m, 2H),3.89 (dd, J=4.3, 9.8 Hz, 1H), 3.82 (q, J=7.3 Hz, 2H), 3.46 (s, 3H),3.18-3.10 (m, 1H), 2.68-2.62 (m, 1H), 2.09 (s, 3H), 2.07-2.02 (m, 1H),1.46 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=300, (M+Na)⁺=322, (M+H—H₂O)⁺=282.

EXAMPLE 175

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-methyl-N-benzylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 7.60-7.47 (m, 5H), 5.75-5.65 (m, 1H), 5.39 (d, J=6.35Hz, 1H), 5.21 (d, J=8.8 Hz, 1H), 5.18-5.11 (m, 1H), 5.00-4.70 (m, 2H),435-4.27 (m, 1H), 4.00-3.94 (m, 2H), 3.86-3.79 (m, 1H), 3.40 (s, 3H),3.14-3.05 (m, 1H), 2.77-2.50 (m, 1H), 2.08 (s, 3H), 2.10-2.94 (m, 1H).

MS: (M+H)⁺=362, (M+Na)⁺=385, (M−H)⁻=360, (M+35)⁻=396.

EXAMPLE 176

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N,N-diethylamino-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.84-5.78 (m, 1H), 5.45 (d, J=16.85 Hz, 1H), 5.26 (d,J=10.0 Hz, 1H), 5.09-5.05 (m, 1H), 4.45-4.42 (m, 1H), 3.96-3.86 (m, 3H),3.76 (q, J=6.6 Hz, 2H), 3.70 (q, J=7.3 Hz, 2H), 3.15-3.11 (m, 1H),2.68-2.62 (m, 1H), 2.08-2.02 (m, 1H), 2.08 (s, 3H), 1.44-1.38 (m, 6H).

MS: (M+H)⁺=314, (M+Na)⁺=336, (M+2Na)⁺=358.

EXAMPLE 177

(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-2-(N-pyrrolidinyl-N-oxide))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.74 (d, 1H), 5.65-5.80 (m, 1H), 5.28 (d, 1H), 5.10(d, 1H), 4.82 (m, 1H), 4.40-4.50 (dd, 1H), 4.30 (d, 1H), 3.60-4.12 (brm,5H), 2.98-3.15 (m, 1H), 2.38-2.48 (m, 1H), 2.05-2.20 (brm, 5H),1.88-1.98 (m, 1H), 1.87 (s, 3H).

MS: (M+H)⁺=312.

EXAMPLE 178

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-morpholinyl-N-oxide)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (DMSO-d₆) δ 8.65 (d, 1H), 5.66-5.80 (m, 1H), 5.22 (d, 1H), 5.09(d, 1H), 4.78 (brs, 1H), 4.32-4.42 (dd, 1H), 4.10-4.17 (brm, 2H),3.50-4.02 (brm, 9H), 2.92-3.04 (brm, 1H), 2.37-2.48 (m, 1H), 1.88-1.96(m, 1H), 1.87 (s, 3H).

MS: (M+H)⁺=328.

EXAMPLE 179(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

179A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-oxiranyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 123I, substituting ethyltriphenylphosphonium bromide in place ofmethyltriphenylphosphonium bromide (yield: 350 mg, 77%).

¹H NMR (CDCl₃) (rotamers) δ 5.55-5.43 (m, 2H), 4.13-4.04 (m, 2H),3.14-3.11 (m, 2H), 2.76-2.50 (m, 3H), 1.75-1.70 (m, 1H), 1.64 (d, 3H),1.48-1.43 (m, 18H).

MS: (M+H)⁺=354, (M+Na)⁺=376, (2M+Na)⁺=729.

179B(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 123J, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-oxiranyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido)butyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 1.08 g, 84%).

¹H NMR (DMSO-d₆) (rotamers) δ 5.53-5.33 (m, 2H), 5.05-4.93 (m, 1H),4.20-3.90 (m, 2H), 3.76-3.62 (m, 2H), 3.24 (s, 3H), 2.59-2.49 (m, 1H),1.64-1.55 (m, 5H), 1.43-1.36 (m, 18H).

MS: (M+H)⁺=475, (M+Na)⁺=497, (2M+Na)⁺=971.

179C(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-aziridinyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 123K, substituting(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (crude yield: 564 mg, 71%).

¹H NMR (DMSO-d₆) (rotamers) δ 5.45-5.30 (m, 2H), 4.15-3.99 (m, 1H),3.30-3.08 (m, 1H), 3.07-2.84 (m, 1H), 2.68-2.51 (m, 1H), 2.13-1.85 (m,1H), 1.80-1.05 (m, 3H), 1.57 (d, J=5.4 Hz, 3H), 1.41-1.35 (m, 18H).

MS: (M+H)⁺=352, (M+23)⁺=375, (2M+H)⁺=705, (2M+23)⁺=727.

179D(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2N-acetylaziridinyl)-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 123L, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-aziridinyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 455 mg, 72%).

¹H NMR (DMSO-d₆) (rotamers) δ 5.74-5.34 (m, 2H), 4.17 (dd, J=2.4, 6.35Hz, 1H), 3.41 (dd, J=1.95, 6.35 Hz, 1H), 3.14-2.99 (m, 1H), 2.73-2.58(m, 2H), 2.40 (d, J=6.35 Hz, 1H), 2.17-2.12 (m, 1H), 2.05-2.00 (m, 3H),1.66-1.55 (m, 1H), 1.56 (d, J=6.8 Hz, 3H), 1.41-1.31 (m, 18H).

MS: (M+H)⁺=395, (M+Na)⁺=417, (M+H+Na)⁺=418.

179E(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-N-ethyl-N-methylamino)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 150, substituting N-ethyl-N-methylamine in place of diethylamine(yield: 30 mg, 87%).

MS: (M+H)⁺=454, (M+Na)⁺=476, (M−H)⁻=452, (M+35)⁻=488.

179E (±)-(2R,3S,5R,1′S,3′R) and(±)-(2R,3S,5R,1′S,3′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 165A, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-(N-ethyl-N-methylamino))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-N-methyl-N-t-butylamino)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 15.2 mg, 51%).

179F(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-2-(N-ethyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′S,3′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-(N-methyl-N-ethyl-N-oxide))ethyl-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3R,5R,1′S)-2-(1-acetamido-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 8.7 mg, 29%).

¹H NMR (MeOD-d₃) δ 5.75-5.69 (m, 1H), 5.37-5.30 (m, 1H), 5.07-5.04 (m,1H), 4.49 (dd, J=7.8, 10.2 Hz, 1H), 4.05-3.74 (m, 4H), 3.61-3.32 (m,1H), 3.55 (s, 3H), 2.69-2.60 (m, 1H), 2.04 (s, 3H), 1.95-1.84 (m, 1H),1.75 (dd, J=2.0, 7.1 Hz, 3H), 1.44 (t, J=7.1 Hz, 3H).

MS: (M+H)⁺=314, (M+35)⁺=348.

EXAMPLES 179-184

The following title compounds were prepared according to the methoddescribed in Example 179.

EXAMPLE 180

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-ethyl-N-ethylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicHydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.75-5.69 (m, 1H), 5.38-5.30 (m, 1H), 5.02-4.98 (m,1H), 4.47 (dd, J=7.8, 9.8 Hz, 1H), 4.02-3.77 (m, 4H), 3.56-3.39 (m, 1H),3.47 (s, 3H), 2.69-2.59 (m, 1H), 2.07 (s, 3H), 1.95-1.84 (m, 1H), 1.76(dd, J=1.7, 7.1 Hz, 3H), 1.46 (t, J=7.1 Hz, 3H).

MS: (M+H)⁺=314, (M+35)⁺=348.

EXAMPLE 181

(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.76-5.66 (m, 1H), 5.39-5.31 (m, 1H), 5.17-5.11 (m,1H), 4.51 (dd, J=7.5, 10.2 Hz, 1H), 4.07-3.76 (m, 4H), 3.55 (s, 3H),3.52-3.39 (m, 1H), 2.69-2.60 (m, 1H), 2.02 (s, 3H), 2.08-1.84 (m, 1H),1.75 (dd, J=1.7, 7.1 Hz, 3H), 1.50 (d, J=6.1 Hz, 3H), 1.48 (d, J=6.4 Hz,3H).

MS: (M+H)⁺=314, (M+35)⁺=348.

EXAMPLE 182

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.76-5.68 (m, 1H), 5.39-5.31 (m, 1H), 5.10-5.05 (m,1H), 4.49 (dd, J=7.8, 9.8 Hz, 1H), 4.12-3.84 (m, 4H), 3.55-3.44 (m, 1H),3.41 (s, 3H), 2.69-2.60 (m, 1H), 2.08 (s, 3H), 2.07-1.84 (m, 1H), 1.76(dd, J=1.7, 6.8 Hz, 3H), 1.51 (d, J=2.4 Hz, 3H), 1.49 (d, J=2.4 Hz, 3H).

MS: (M+H)⁺=314, (M+35)⁺=348.

EXAMPLE 183

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-isobutyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.75-5.69 (m, 1H), 5.38-5.31 (m, 1H), 5.18-5.12 (m,1H), 4.53 (dd, J=7.5, 9.8 Hz, 1H), 4.25-3.42 (m, 6H), 3.65 (s, 3H),2.68-2.58 (m, 1H), 2.44-2.36 (m, 1H), 2.05 (s, 3H), 1.94-1.87 (m, 1H),1.76 (d, J=2.7 Hz, 3H), 1.14 (d, J=6.8 Hz, 6H).

MS: (M+H)⁺=342, (M+Na)⁺=364, (M−H)⁻=340.

EXAMPLE 184

(±)(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-2N-isobutyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

¹H NMR (MeOD-d₃) δ 5.75-5.69 (m, 1H), 5.38-5.31 (m, 1H), 5.06-5.02 (m,1H), 4.48 (dd, J=7.5, 9.8 Hz, 1H), 4.08-3.85 (m, 3H), 3.70-3.57 (m, 2H),3.52 (s, 3H), 3.48-3.41 (m, 1H), 2.70-2.60 (m, 1H), 2.40-2.36 (m, 1H),2.08 (s, 3H), 1.95-1.84 (m, 1H), 1.75 (dd, J=1.7, 7.1 Hz, 3H), 1.14 (d,J=6.8 Hz, 6H).

MS: (M+H)⁺=342, (M+Na)⁺=364, (M−H)⁻=340.

EXAMPLE 185(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-isopropyl-N-hydroxyamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

165A(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2N-isopropyl-N-hydroxyamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-isopropylamino)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (21 mg, 0.048 mmole) was dissolved in 0.95 mL ofacetone. It was then titrated with 0.14 mL of a solution ofdimethyldioxirane (0.1 M) in acetone at 45° C. for 0.5 hour. Thereaction was stopped by concentrating the mixture in vacuo. The residuewas purified by chromatography on silica gel using 100% dichloromethaneto 90% dichloromethane/methanol to provide the title compound (yield:5.3 mg, 24%) and recovered starting material (yield 12 mg, 57%).

¹H NMR (MeOD-d₃) δ 5.95-5.89 (m, 1H), 5.08-4.94 (m, 2H), 4.75-4.68 (m,1H), 4.13-3.83 (m, 2H), 2.85-2.47 (m, 4H), 1.96 (s, 3H), 1.82-1.76 (m,1H), 1.52-1.44 (m, 18H), 1.45-1.29 (m, 1H), 1.07-1.04 (m, 6H).

MS: (M+H)⁺=456, (M+Na)⁺=478, (M−H)⁻=454, (M+35)⁻=490.

185B(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(N-isopropyl-N-hydroxyamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-(N-isopropyl-N-hydroxyamino))ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.0 mg, 87%).

¹H NMR (MeOD-d₃) δ 5.83-5.71 (m, 1H), 5.40 (d, J=17.3 Hz, 1H), 5.24 (d,J=10.2 Hz, 1H), 4.48 (dd, J=7.8, 10.2 Hz, 1H), 3.88-3.59 (m, 4H),3.17-3.10 (m, 1H), 2.67-2.58 (m, 1H), 2.10-1.99 (m, 1H), 2.09 (s, 3H),1.33-1.17 (m, 1H), 1.38 (d, J=6.4 Hz, 6H).

MS: (M+H)⁺=300, (M−H)⁻=298, (2M−H)⁻=597.

EXAMPLE 186

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)-2-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo-2-phenyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 5.9 mg, 100%).

¹H NMR (DMSO-d₆) δ 8.62 (d, J=9.8 Hz, 1H), 7.93 (m, 2H), 7.68 (m, 1H),7.55 (t, J=7.9 Hz, 2H), 5.61 (m, 1H), 5.48 (m, 1H), 5.19 (m, 1H), 4.50(m, 1H), 3.98 (t, J=9.8 Hz, 1H), 3.30 (m, 1H), 2.38 (m, 1H), 1.73 (m,1H), 1.71 (s, 3H), 1.59 (m, 3H).

MS: (M+H)⁺=331, (M+Na)⁺=353, (M−H)⁻=329.

EXAMPLE 187(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

187A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

187B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound is prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 188(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

188A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxyvinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0044 g, 22%).

MS: (M+H)⁺=481, (M−H)⁻=479.

188B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0031 g, 100%).

¹H NMR (DMSO-d₆) δ 7.93 (d, J=9.2 Hz, 1H), 5.81 (m, 1H), 5.49 (m, 1H),5.26 (m, 1H), 5.1-4.9 (m, 2H), 4.29 (m, 1H), 4.03 (m, 2H), 3.68 (m, 1H),3.26 (m, 1H), 3.25 (s, 3H), 3.18 (quint., J=8.5 Hz, 1H), 2.40 (dt,J=12.7, 7.3 Hz, 1H), 2.32 (m, 1H), 2.20 (m, 1H), 2.02 (m, 1H), 1.85 (s,3H), 1.68 (m, 1H), 1.64 (m, 1H), 1.61 (dd, J=6.7, 1.8 Hz, 3H), 1.55-1.40(m, 2H).

MS: (M+H)⁺=325, (M+Na)⁺=347, (M−H)⁻=323.

EXAMPLE 189 (±)-(2R,3

¹H NMR (DMSO-d₆) (rotamers) δ 7.62-7.58 (m, 4H), 7.49-7.38 (m, 6H),4.97-4.79 (m, 1H), 4.19-4.02 (m, 2H), 3.79-3.48 (m, 2H), 3.15 and 3.13(2s, 3H), 2.49-2.39 (m, 2H), 1.98-1.74 (m, 1H), 1.43-1.25 (m, 18H), 1.02and 1.00 (2s, 9H).

MS: (M+H)⁺=703, (M+Na)⁺=725.

189B(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-aziridinyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester

The title compound was prepared according to the method described inExample 123K substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-methanesulfonyloxy-3-azido)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 5.9 g, 79%).

¹H NMR (DMSO-d₆) (rotamers) δ 7.60-7.56 (m, 4H), 7.49-7.39 (m, 6H),4.11-4.05 (m, 1H), 3.67-3.48 (m, 2H), 3.42-3.30 (m, 1H), 2.49-2.39 (m,1H), 2.25-1.61 (m, 5H), 1.40, 1.35, 1.33, and 1.27 (4s, 18H), 0.99 and0.98 (2s, 9H).

MS: (M+H)⁺=581, (M+Na)⁺=603.

189C(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-N-acetylaziridinyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 123L substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-aziridinyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.1 g, 96%).

¹H NMR (DMSO-d₆) (rotamers) δ 7.60-7.57 (m, 4H), 7.49-7.39 (m, 6H),4.18-4.11 (m, 1H), 3.71-3.51 (m, 3H), 2.76-2.68 (m, 1H), 2.58-2.45 (m,1H), 2.46 and 2.39 (2d, J=6.1, 6.1 Hz, 1H), 2.40 and 2.47 (2m, 1H), 2.08and 2.05 (2d, J=3.1, 3.1 Hz, 1H), 2.02 and 1.99 (2s, 3H), 1.94-1.79 (m,1H), 1.41, 1.36, 1.35 and 1.29 (4s, 18H), 0.99 and 0.98 (2s, 9H).

MS: (M+H)⁺=623, (M+Na)⁺=645.

189D(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-acetoxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-N-acetylaziridinyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (2.75 g, 4.40 mmole) was reacted with potassiumacetate (2.49 g, 25.37 mmole) and acetic acid (1.45 mL, 25.37 mmole) inDMSO (45 mL) at 100° C. for 16 hours. The reaction was quenched with 1NNaHCO₃ (100 mL) and diluted with ethyl acetate (300 mL). The organiclayer was washed with water and brine, dried over MgSO₄, filtered andconcentrated in vacuo. The residue was purified by chromatography onsilica gel using 100% dichloromethane to 50% dichloromethane/ethylacetate to provide the title compound (yield: 2.45 g, 81%).

MS: (M+H)⁺=683, (M+Na)⁺=705, (M−H)⁻=681, (M+Cl)⁻=717.

189E(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-acetoxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (2.45 g, 3.58 mmole) was reacted with potassiumcarbonate (1.48 g, 10.73 mmole) in methanol (18 mL) and THF (18 mL) at25° C. for 45 minutes. The reaction was quenched with water (100 mL) anddiluted with ethyl acetate (200 mL). The organic layer was washed withwater,and brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel using 85%dichloromethane/ethyl acetate to 100% ethyl acetate to provide the titlecompound (yield: 2.05 g, 90%).

MS: (M+H)⁺=641, (M+Na)⁺=663, (2M+Na+H)⁺=1304, (M−H)⁻=639, (M+Cl)⁻=675.

189F(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 41A substituting(±)-(2R,3R,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of (±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆) (rotamers) 9.49 (d, J=16.3, 1H), 8.33 and 8.29 (2d,J=8.8 and 8.8 Hz, 1H), 7.58-7.38 (m, 10H), 4.94 and 4.84 (2dd, J=4.4,8.8 Hz and 4.4, 8.8 Hz, 1H), 4.26-3.37 (m, 4H), 2.47-2.30 (m, 1H),1.97-1.83 (m, 1H), 1.92 (s, 3H), 1.42-1.18 (m, 18H), 1.42-1.18 (m, 1H),1.00-0.97 (m, 9H).

MS: (M+H)⁺=639, (M−H)⁻=637.

189G(±)-(2R,3R,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-vinyl)methyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 118A substituting(±)-(2R,3R,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of (±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆) (rotamers) 7.99-7.74 (m, 1H), 7.59-7.39 (m, 10H),5.80-5.68 (m, 1H), 5.21-5.01 (m, 3H), 3.97-3.31 (m, 1H), 3.78-3.74 (m,1H), 3.60-3.46 (m, 2H), 2.53-2.37 (m, 1H), 2.09-1.72 (m; 1H), 1.87 (s,3H), 1.42-1.23 (m, 19H), 1.00-0.99 (m, 9H).

189H (±)-(2R,3R,5R,1′R,2′R) and(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2,3-dihydroxy)propyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compounds were prepared according to the method described inExample 20A substituting(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-vinyl)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R)-1-benzyl-2-vinyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (±)-(2R,3R,5R,1′R,2′S) isomer (yield: 311 mg, 24%)(±)-(2R,3R,5R,1′R,2′R) isomer (yield: 700 mg, 54%).

(±)-(2R,3R,5R,1′R,2′S) ¹H NMR (DMSO-d₆) (rotamers) 7.62-7.39 (m, 11H),4.56 and 4.51 (d, J=4.8, 1H), 4.46-4.39 (m, 2H), 3.97-3.82 (m, 1H),3.74-3.47 (m, 3H), 3.28-3.21 (m, 2H), 2.89-2.64 (m, 1H), 2.51-2.45 (m,1H), 2.05-1.8 (m, 1H), 1.87-1.86 (m, 3H), 1.43-1.23 (m, 19H), 0.99-0.98(m, 9H).

(±)-(2R,3R,5R,1′R,2′R) ¹H NMR (DMSO-d₆) (rotamers) 7.63-7.40 (m, 11H),4.56-4.54 (d, J=4.8, 1H), 4.47-4.33 (m, 2H), 3.94-3.80 (m, 1H),3.85-3.80 (m, 1H), 3.76-3.68 (m, 1H), 3.60-3.51 (m, 1H), 3.44-3.35 (m,1H), 3.30-3.21 (m, 1H), 2.78-2.62 (m, 1H), 2.46-2.31 (m, 1H), 2.07-1.98(m, 1H), 1.83 (s, 3H), 1.39-1.29 (m, 19H), 1.00-0.99 (m, 9H).

189I(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2,3-dihydroxy)propyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester was reacted with 2,2-dimethoxypropane (1.1 ml, 9.09mmole) and p-Toluenesulfonic acid (4.3 mg, 0.023 mmole) intetrahydrofuran (4.5 mL) at 25° C. for 45 minutes. The reaction wasquenched with triethylamine (3 mL). Stirring was continued for anadditional 10 minutes. The reaction was then diluted with 10% NaHCO₃ (15mL) and extracted with ethyl acetate (45 ml). The organic layer waswashed with water,and brine, dried over MgSO₄, filtered and concentratedin vacuo. The residue was carried over to the next step, purified bychromatography on silica gel using 100% dichlormethane to 94%dichloromethane/methanol to provide the title compound (yield: 194 mg,91%).

189J(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 123G substituting(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester. The resulting residue was purified by chromatographyon silica gel using 100% dichlormethane to 94% dichloromethane/methanolto provide the title compound (yield: 194 mg, 91%).

189JJ(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methylformyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 123H substituting(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

189K(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-(cis-propen-1-yl))-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 35A substituting(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 11.5 mg, 59%).

¹H NMR (CDCl₃): δ 6.62 (d, 1H), 5.56 (m, 1H), 5.40 (m, 1H), 4.43 (m,1H), 4.25 (m, 1H), 4.16 (m, 1H), 4.02 (m, 1H), 3.88 (m, 1H), 3.54 (m,1H), 3.14 (m, 1H), 2.54 (m, 1H), 2.04 (s, 3H), 1.71 (m, 1H), 1.60 (dd,3H), 1.46 (s, 9H), 1.45 (s, 9H), 1.40 (s, 3H), 1.32 (s, 3H).

MS: (M+H)⁺=483.

189L(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2,3-dihydroxy)-propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 7.84 (d, J=9 Hz, 1H), 5.49 (m, 1H), 5.27 (m, 1H),4.47 (m, 1H), 4.25 (m, 1H), 4.17 (m, 1H), 3.75 (m, 1H), 3.59 (m, 1H),3.35 (m, 1H), 3.18 (m, 1H), 2.43 (m, 1H), 1.81 (s, 3H), 1.55 (dd, 3H).

MS: (M+H)⁺=287.

EXAMPLE 190(±)-(2R,3R,5R,1′R,2′R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

190A(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-t-butyldithenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 1891 substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2,3-dihydroxy)propyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2,3-dihydroxy)propyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

190B(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-hydroxyethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 123G substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

190C(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 123H substituting(±)-(2R,3R,6R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

190D(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-(cis-propen-1-yl))-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 35A substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 42 mg, 61%).

¹H NMR (CDCl₃): δ 7.88 (d, 1H), 5.52 (m, 1H), 5.34 (m, 1H), 4.33 (m,1H), 4.21 (m, 1H), 3.96 (m, 2H), 3.83 (m, 1H), 3.60 (m, 1H), 3.40 (m,1H), 2.53 (m, 1H), 1.98 (s, 3H), 1.66 (dd, 3H), 1.46 (s, 9H), 1.44 (s,9H), 1.41 (s, 3H), 1.33 (s, 3H).

MS: (M+H)⁺=483.

190E(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2,3-dihydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-1-(2,2-dimethyl-1,3-dioxolan-4-yl))methyl-3-(cis-propen-1-yl))-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5S,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (DMSO-d₆): δ 7.98 (d, J=9 Hz, 1H), 5.48 (m, 1H), 5.29 (m, 1H),4.60 (m, 1H), 4.30 (m, 1H), 4.12 (m, 1H), 3.76 (m, 1H), 3.52 (m, 1H),3.46 (m, 1H), 3.32 (m, 1H), 3.18 (m, 1H), 2.40 (m, 1H), 1.84 (s, 3H),1.60 (dd, 3H).

MS: (M+H)⁺=287.

EXAMPLE 193(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

193A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 88A, substituting ethyl iodide for methyl iodide (yield: 3.6 mg,28%).

MS: (M+H)⁺=483, (M+Na)⁺=505, (M−H)⁻=481.

193B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. ester (yield: 3.2 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.92 (d, J=9.2 Hz, 1H), 5.47 (m, 1H), 5.25 (m, 1H),4.25 (m, 2H), 3.70 (m, 1H), 3.52 (m, 1H), 3.33 (m, 2H), 3.18 (m, 1H),2.39 (m, 1H), 1.85 (s, 3H), 1.66 (m, 1H), 1.61 (dd, J=6.7, 1.8 Hz, 3H),1.56 (m, 1H), 1.37 (m, 1H), 1.28 (m, 2H), 1.13 (m, 3H), 0.86 (t, J=7.3Hz, 3H).

MS: (M+H)⁺=327, (M+Na)⁺=349, (M−H)⁻=325.

EXAMPLE 194(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

194A(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound is prepared according to the method described inExample 88A, substituting ethyl iodide for methyl iodide.

194B(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound is prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 195(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 19.9 mg, 100%).

¹H NMR (DMSO-d₆) δ 7.80 (d, J=8.8 Hz, 1H), 5.76 (m, 1H), 5.23 (d, J=17.1Hz, 1H), 5.15 (m, 1H), 4.31 (m, 1H), 4.03 (m, 1H), 3.62 (m, 1H), 3.53(m, 2H), 2.79 (m, 1H), 2.42 (m, 1H), 1.90 (s, 3H), 1.85 (m, 1H).

MS: (M+H)⁺=243, (M+Na)⁺=265, (M−H)⁻=241.

EXAMPLE 196(±)-(2R,3S,5R,1′R,2′S)-(2R-(1-Acetamido-2-hydroxy-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

196A (±)-(2R,3S,5R,1′R,2′S) and(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (78 mg, 0.19 mmol) in THF (5 mL) was added dropwiseto a solution of dimethylphosphonylmethyl lithium (3M) (0.32 mL, 0.95mmol) in THF (20 mL) at −78° C. and reacted for 40 minutes. The reactionwas quenched with water (10 mL) and saturated aqueous ammonium chloride(10 mL) followed by extraction using dichloromethane (2×50 mL). Theorganic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 5-10% methanol in dichloromethane to provide thetitle compounds (±)-(2R,3S,5R,1′R,2′R) isomer (yield: 27 mg, 27%) and(±)-(2R,3S,5R,1′R,2′S) isomer (yield: 5.5 mg, 6%).

(±)-(2R,3S,5R,1′R,2′R)=¹H NMR (CDCl₃) δ 5.98 (m, 1H), 5.58 (m, 1H), 5.35(m, 1H), 4.94 (m, 1H), 4.14 (m, 2H), 3.74 (m, 8H), 3.06 (m, 1H), 2.64(m, 1H), 2.03 (s, 3H), 1.95 (m, 1H), 1.83 (m, 3H), 1.53 (s, 9H), 1.46(s, 9H).

MS: (M+H)⁺=535, (M−H)⁻=533.

(±)-(2R,3S,5R,1′R,2′S) MS: (M+H)⁺=535, (M−H)⁻=533.

196B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxylmethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3 mg, 96%).

¹H NMR (DMSO-d₆) δ 7.98 (d, J=9.2 HZ, 1H), 5.48 (m, 1H), 5.28 (m, 1H),4.36 (m, 1H), 4.30 (m, 1H), 4.08 (m, 2H), 3.70 (m, 2H), 3.60 (m, 6H),3.18 (m, 1H), 2.40 (m, 1H), 2.05 (m, 1H), 1.85 (s, 3H), 1.60 (dd, J=6.2,1.2 HZ, 3H).

MS: (M+H)⁺=379, (M−H)⁻=377.

EXAMPLE 197

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-3-dimethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxylmethylphosphonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 13 mg, 96%).

¹H NMR (DMSO-d₆) δ 7.72 (d, J=9.2 HZ, 1H), 5.48 (m, 1H), 5.24 (m, 1H),4.44 (m, 1H), 4.15 (m, 2H), 3.62 (m, 7H), 3.54 (m, 1H), 3.15 (m, 1H),2.40 (m, 1H), 1.95 (m, 1H), 1.82 (s, 3H), 1.72 (m, 1H), 1.54 (dd, J=6.7,1.2 HZ, 3H).

MS: (M+H)⁺=379, (M−H)⁻=377.

EXAMPLE 198(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

198A (±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(cis andtrans-2-methoxyvinyl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (113 mg, 0.28 mmol) was added to a solution of(methoxymethyl)triphenylphosphonium bromide (240 mg, 0.70 mmol) andpotassium t-butoxide (0.56 mL, 0.56 mmol, 1M in THF) in toluene (3 mL)at 0° C. for 15 minutes. The reaction was quenched with saturatedaqueous ammonium chloride (3 mL) followed by extraction usingdichloromethane (2×3 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel using 1/4: ethyl acetate/hexane toprovide the title compounds.

¹H NMR (CDCl₃) δ 8.65 (br d, 1H), 6.01 (d, J=5.7 Hz, 1H), 5.40 (m, 3H),5.11 (br t, 1H), 4.15 (m, 2H), 3.72 (m, 1H), 3.61 (s, 3H), 3.00 (m, 1H),2.42 (m, 1H), 1.94 (s, 3H), 1.64 (dd, J=1.4, 5.0 Hz, 3H), 1.45 (m, 9H),1.25 (m, 9H).

MS: (M+H)⁺=439.

198B(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-(cis andtrans-2-methoxyvinyl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (21 mg, 0.048 mmol) was reacted with LiBr (37 mg,0.43 mmol) and AG50W-X2 ion exchange resin in CH₃CN (2 mL) and water(0.1 mL) at room temperature for 45 minutes. The reaction was filteredand quenched with saturated aqueous sodium bicarbonate (1 mL) followedby extraction using dichloromethane (2×1 mL). The organic layer wasdried over magnesium sulfate, filtered and concentrated in vacuo. Theresidue was purified by column chromatography on silica gel using 1/4:ethyl acetate/hexane to provide the title compound.

¹H NMR (CDCl₃) δ 9.70 (dd, J=1.3, 2.4 Hz, 1H), 8.11 (d, J=7.8 Hz, 1H),5.54 (m, 1H), 5.41 (t, J=5.8 Hz, 1H), 4.52 (m, 1H), 4.13 (dd, J=4.4, 4.8Hz, 1H), 3.75 (dd, J=2.7, 3.1 Hz, 1H), 2.86 (m, 1H), 2.47 (m, 3H), 1.99(s, 3H), 1.63 (dd, J=1.6, 5.1 Hz, 3H), 1.46 (s, 9H), 1.45 (m, 1H), 1.44(s, 9H).

MS: (M+H)⁺=425, (M−H)⁻=423.

198C(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (9 mg, 0.02 mmol) was reacted with sodium borohydride(1 mg, 0.02 mmol) in methanol (0.1 mL) at room temperature for 20minutes. The reaction was quenched with saturated aqueous ammoniumchloride (1 mL) followed by extraction using dichloromethane (2×1 mL).The organic layer was dried over magnesium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 1/4: ethyl acetate/hexane to provide the titlecompound.

¹H NMR (CDCl₃) δ 8.45 (d, J=7.5 Hz, 1H), 5.55 (m, 1H), 5.34 (t, J=7.8Hz, 1H), 4.20 (dd, J=3.0, 5.4 Hz, 2H), 3.71 (d, J=6.1 Hz, 1H), 3.62 (m,1H), 3.50 (t, J=9.1 Hz, 1H), 2.92 (m, 1H), 2.41 (m, 1H), 2.04 (s, 3H),1.66 (dd, J=2.0, 5.1 Hz, 3H), 1.62 (m, 1H), 1.47 (s, 9H), 1.45 (m, 1H),1.43 (s, 9H), 1.22 (m, 2H).

MS: (M+H)⁺=427; (M−H)⁻=425.

198D(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. ester (yield: 4.6 mg, 100%).

¹H NMR (DMSO-d₆) δ 9.25 (br s, 1H), 8.13 (d, J=7.3 Hz, 1H), 5.52 (m,1H), 5.28 (br t, 1H), 4.32 (br t, 1H), 4.22 (m, 1H), 3.49 (m, 4H), 3.18(m, 1H), 2.40 (m, 1H), 1.90 (s, 3H), 1.73 (m, 1H), 1.63 (dd, J=1.8, 5.5Hz, 3H), 1.57 (m, 1H).

MS: (M−H)⁻=269; (M+H)⁺=271.

EXAMPLE 199(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

199A (±)-(2R,3S,5R,1′S,3′S) and(±)-(2R,3S,5R,1′R,3′R)-1-t-Butoxycarbonyl-2-(1-acetamido-3-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (26 mg, 0.061 mmol) was reacted with ethylmagnesiumbromide (3.0 M) (0.122 mL, 0.367 mmol) in THF (4 mL) at room temperaturefor 30 minutes. The reaction was quenched with saturated aqueousammonium chloride (10 mL) and water (10 mL) followed by extraction usingethyl acetate (3×25 mL). The organic layer was dried over magnesiumsulfate, filtered and concentrated in vacuo. The residue was purified bycolumn chromatography on silica gel using 1/1 ethyl acetate/hexanefollowed by 2/1 ethyl acetate/hexane to provide the title compounds(±)-(2R,3S,5R,1′S,2′S) (yield: 6.7 mg, 24%) and (±)-(2R,3S,5R,1′S,2′R)(yield: 6.8 mg, 24%).

(±)-(2R,3S,5R,1′S,2′S) MS: (M+H)⁺=455, (M+Na)⁺=477, (M−H)⁻=453.

(±)-(2R,3S,5R,1′S,2′R) MS: (M+H)⁺=455, (M+Na)⁺=477, (M−H)⁻=453.

199B(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituing(±)-(2R,3S,5R,1′S,3′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. ester (yield: 6.2 mg, 100%).

¹H NMR (DMSO-d₆) δ 9.20 (bs, 1H), 8.18 (d, J=7.3 Hz, 1H), 5.51 (m, 1H),5.27 (m, 1H), 4.30 (m, 1H), 4.25 (m, 1H), 3.58 (m, 1H), 3.41 (m, 1H),3.18 (m, 1H), 2.39 (m, 1H), 1.90 (s, 3H), 1.75 (m, 1H), 1.64 (dd, J=7.5,1.5 Hz, 3H), 1.51 (m, 1H), 1.38 (m, 1H), 1.32 (m, 1H), 0.83 (t, J=7.3Hz, 3H).

MS: (M+H)⁺=299, (M+Na)⁺=321, (M−H)⁻=297, (2M−H)⁻=595.

EXAMPLE 200(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′S,3′R)-1-t-butoxycarbonyl-2-(1-acetamido-3-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. ester (yield: 6.5 mg, 100%).

¹H NMR (DMSO-d₆) δ 9.25 (bs, 1H), 8.15 (d, J=7.3 Hz, 1H), 5.52 (m, 1H),5.27 (m, 1H), 4.31 (m, 2H), 3.52 (m, 1H), 3.36 (m, 1H), 3.19 (quint.,J=8.5 Hz, 1H), 2.38 (m, 1H), 1.92 (s, 3H), 1.75 (m, 1H), 1.64 (dd,J=7.3, 1.5 Hz, 3H), 1.48 (m, 1H), 1.33 (m, 2H), 0.85 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=299, (M+Na)⁺=321, (M−H)⁻=297, (2M−H)⁻=595.

EXAMPLE 201(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-oxo-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-Acetamido-2-oxo-3,3-difluoro-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0050 g, 100%).

¹H NMR (DMSO-d₆) δ 8.67 (d, J=8.5 Hz, 1H), 6.1-5.95 (m, 1H), 5.78 (dd,J=7.1, 2.4 Hz, 1H), 5.71 (d, 11.0 Hz, 1H), 5.45 (m, 1H), 5.12 (m, 1H),4.94 (t, J=9.2 Hz, 1H), 4.51 (dd, J=12.2, 6.1 Hz, 1H), 3.98 (m, 1H),3.24 (m, 1H), 2.32 (m, 1H), 1.73 (s, 3H), 1.66 (q, J=11.99 Hz, 1H), 1.57(dd, J=6.7, 1.8 Hz, 3H).

MS: (M+H)⁺=331, (M+H₂O)⁺=349, (M+Na)⁺=353, (M−H)⁻=329, (2M−H)⁻=659.

EXAMPLE 202

202A (±)-(2R,3R,5R,1′R,2′S) and(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compounds were prepared according to the method described inExample 41B substituting(±)-(2R,3R,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-formyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester to provide (±)2R,3R,5R,1′R,2′S) isomer (yield: 370mg, 17%) and (±)-(2R,3R,5R,1′R,2′R) isomer (yield: 1.2 g, 55%).

(±)-(2R,3R,5R,1′R,2′S) ¹H NMR (d₆-DMSO) δ 7.4-7.65 (m, 10H), 4.47 (d,1H), 4.32 (m, 1H), 3.87 (m, 2H), 3.68 (m, 1H), 3.55 (m, 1H), 3.25 (m,1H), 2.7 (m, 1H), 2.45 (m, 1H), 2.0 (m, 1H), 1.83 (d, 3H), 1.28-1.4 (m,18H), 0.95 (d, 9H), 0.83 (dt, 3H).

MS: (M−H)−=667, (M+35)⁺=703; (M+H)⁺=669, (M+Na)+=691.

(±)-(2R,3R,5R,1′R,2′R) ¹H NMR (d₆-DMSO) δ 7.4-7.65 (m, 10H), 4.40 (dd,1H), 4.12-4.32 (m, 1H), 3.82-3.96 (m, 1H), 3.66 (m, 2H), 3.52 (t, 1H),2.6-2.8 (m, 1H), 2.45 (m, 1H), 1.76-2.0 (m, 1H), 1.87 (d, 3H), 1.25-1.4(m, 18H), 0.95 (d, 9H), 0.83 (dt, 3H).

MS: (M−H)−=667, (M+35)⁺=703; (M+H)⁺=669, (M+Na)+=691.

202B(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (0.58 g, 0.87 mmole) was reacted with methoxymethylchloride (1.15 mL, 10.07 mmole) and diisopropylethylamine (3.5 mL, 20.1mmole) in dichloromethane (1 mL) at room temperature for 5 hours. Thereaction was quenched with saturated NH₄Cl (100 mL) and diluted withethyl acetate (200 mL). The organic layer was washed with water, andbrine, dried over MgSO₄, filtered and concentrated in vacua. The residuewas purified by chromatography on silica gel using 5% methanol/methylenechloride to provide the title compound (yield: 0.64 g, 98%).

¹H NMR (d₆-DMSO) δ 7.4-7.65 (m, 10H), 4.70 (s, 1H), 4.62 (s, 1H),4.35-4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.68 (m, 1H), 3.55 (m, 1H), 3.25(m, 1H), 3.24 (s, 3H), 2.55 (m, 1H), 2.45 (m, 1H), 2.0 (m, 1H), 1.85 (s,3H), 1.28-1.4 (m, 18H), 0.99 (d, 9H), 0.8 (dt, 3H).

MS: (M−H)−=755, (M+35)⁺=791; (M+H)⁺=757, (M+Na)+=779.

202C(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-hydyroxmethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 123G substituting(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.416 g, 95%).

¹H NMR (d₆-DMSO) δ 7.45 (t, 1H), 4.62-4.74 (m, 3H), 4.48 (m, 1H), 3.85(m, 2H), 3.55-3.6 (m, 2H), 3.45 (t, 1H), 3.2-3.4 (m, 2H), 3.25 (d, 3H),2.4 (m, 2H), 1.82 (d, 3H), 1.58 (m, 3H), 1.32-1.45 (m, 18H), 0.82 (dt,3H).

MS: (M−H)−=517, (M+35)⁺=553; (M+H)⁺=519, (M+Na)⁺=541.

202D(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The tide compound was prepared according to the method described inExample 123H substituting(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.335 g, 80.8%).

¹H NMR (d₆-DMSO) δ 9.55 (d, 1H), 7.48 (m, 1H), 4.55-4.72 (m, 4H), 3.9(d, 1H), 3.6 (m, 2H), 3.45 (m, 3H), 3.32 (s, 3H), 3.05 (t, 1H),2.25-2.45 (m, 4H), 1.83 (s, 3H), 1.58 (m, 3H), 1.30-1.45 (m, 18H), 0.86(dt, 3H).

MS: (M−H)⁻=515, (M+35)⁺=551; (M+H)⁺=517.

202E(±)-(2R,3R,5R,1′R,2′S,1″RS)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 38A substituting(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.27 g, 83%).

MS: (M−H)⁻541, (M+35)⁺=577; (M+H)⁺=543, (M+Na)⁺=565.

202F(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 38B substituting(±)-(2R,3R,5R,1′R,2′S,1″RS)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S,1″RS)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.2 g, 74%).

¹H NMR (d₆-DMSO) δ 7.49 (br d, 1H), 5.0 (d, 1H), 4.7 (br s, 1H),4.55-4.7 (m, 3H), 3.88 (br d, 1H), 3.5-3.7 (m, 2H), 3.43 (t, 2H),3.2-3.4 (m, 2H), 3.24 (s, 3H), 2.4-2.7 (m, 2H), 1.84 (s, 3H), 1.5-1.7(m, 2H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H).

MS: (M−H)⁻=539, (M+35)⁺=575; (M+H)⁺=541, (M+Na)⁺=563.

202G(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 38C substituting(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 180 mg, 87%).

¹H NMR (d₆-DMSO) δ 7.57 (br t, 2H), 6.1 (d, 1H), 4.50-4.7 (m, 4H), 3.95(m, 1H), 3.4-3.6 (m, 3H), 3.3-3.4 (m, 3H), 3.22 (d, 3H), 2.55-2.65 (m,1H), 2.2 (m, 1H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H),0.86 (dt, 3H).

MS: (M−H)⁻=553, (M+35)⁺=589; (M+H)⁺=553, (M+Na)⁺=577.

202H(±)-(2R,3R,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester. Chromatography on silica gel with 2-propanol:aceticacid:ethyl acetate:water 1:1:3:1 followed by the addition of 0.1%trifluoroacetic acid gave the title compound (yield: 15 mg, 55%).

¹H NMR (d₆-DMSO) δ 7.95 (d, 1H), 7.65 (br s, 1H), 6.18 (d, 1H), 1.37 (m,1H), 4.23 (m, 1H), 4.38 (m, 1H), 4.56 (m, 1H), 2.63 (m, 1H), 2.10 (m,1H), 1.78 (s, 3H), 1.50 (m, 1H), 1.25 (m, 1H), 0.83 (t, J=7.46 Hz, 3H).

MS: (M−H)−=309, (M+35)⁺=345; (M+H)⁺=311, (M+Na)+=333.

EXAMPLE 203(±)-(2R,3R,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

203B(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compounds were prepared according to the method described inExample

2028 substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.217 g, 96%).

¹H NMR (d₆-DMSO) δ 7.4-7.65 (m, 10H), 4.70 (s, 1H), 4.62 (s, 1H),4.35-4.55 (m, 2H), 3.75-3.95 (m, 2H), 3.08 (m, 1H), 3.55 (m, 1H), 3.25(m, 1H), 3.24 (s, 3H), 2.55 (m, 1H), 2.45 (m, 1H), 2.0 (m, 1H), 1.85 (s,3H), 1.28-1.4 (m, 18H), 0.99 (d, 9H), 0.8 (dt, 3H).

MS: (M−H)−=755, (M+35)⁺=791; (M+H)⁺=757, (M+Na)+=779.

203C(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 123G substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-oxiranyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.124 g, 83%).

¹H NMR (d₆-DMSO) δ 7.42 (dd, 1H), 4.62-4.8 (m, 3H), 4.48 (m, 1H),3.6-3.85 (m, 3H), 3.35-3.6 (m, 4H), 3.25 (s, 3H), 2.25 (m, 1H), 2.4 (m,1H), 2.28 (m, 1H), 1.82 (s, 3H), 1.58 (m, 3H), 1.32-1.45 (m, 18H), 0.9(dt, 3H).

MS: (M−H)⁻=517, (M+35)⁺=553; (M+H)⁺=519, (M+Na)⁺=541.

203D(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 123H substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-oxiranyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.106 g, 86%).

¹H NMR (d₆-DMSO) δ 9.58 (d, 1H), 7.58 (dd, ₁H), 4.6-4.72 (m, 3H), 4.48(d, 1H), 3.88 (d, 1H), 3.4-3.65 (m, 5H), 3.24 (s, 3H), 3.15 (dd, 1H),2.20-2.48 (m, 4H), 1.86 (s, 3H), 1.58 (m, 3H), 1.30-1.40 (m, 18H), 0.86(t, 3H).

MS: (M−H)⁻=515, (M+35)⁺=551; (M+H)⁺=517.

203E(±)-(42R,3R,5R,1′R,2′R,1″RS)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 38A substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S,1″RS)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 32 mg, 76%).

MS: (M−H)⁻=541, (M+35)⁺=577; (M+H)⁺=543, (M+Na)⁺=565.

203F(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-oxo-2-propyn-1-yl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 38B substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-hydroxy-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S,1″RS)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 25 mg, 78%).

¹H NMR (d₆-DMSO) δ 7.49 (br d, 1H), 5.0 (d, 1H), 4.7 (br s, 1H),4.55-4.7 (m, 3H), 3.88 (br d, 1H), 3.5-3.7 (m, 2H), 3.43 (t, 2H),3.2-3.4 (m, 2H), 3.24 (s, 3H), 2.4-2.7 (m, 2H), 1.84 (s, 3H), 1.5-1.7(m, 2H), 1.30-1.45 (m, 18H), 0.86 (dt, 3H).

MS: (M−H)⁻=539, (M+35)⁺=575; (M+H)⁺=541, (M+Na)⁺=563.

203G(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 38C substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-t-butoxycarbonyl-2-(1-acetamido-3-methyl)butyl-3-(1-oxo-2-propyn-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 18 mg, 72%).

¹H NMR (d₆-DMSO) δ 7.57 (m, 2H), 6.1 (d, 1H), 4.40-4.7 (m, 4H), 3.93 (m,1H), 3.4-3.6 (m, 3H), 3.3-3.4 (m, 3H), 3.22 (d, 3H), 2.55-2.65 (m, 1H),2.2 (m, 1H), 1.85 (s, 3H), 1.5-1.7 (m, 2H), 1.15-1.45 (m, 18H), 0.86 (m,3H).

MS: (M−H)⁻=553, (M+35)⁺=589; (M+H)⁺=553, (M+Na)⁺=577.

203H(±)-(2R,3R,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 15B, substituting(±)-(2R,3R,5R,1′R,2′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxymethyloxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. Chromatography on silica gel with 2-propanol:aceticacid:ethyl acetate:water 1:1:3:1 followed by the addition of 0.1%trifluoroacetic acid gave the title compound (yield: 4 mg, 45%).

¹H NMR (d₆-DMSO) δ 7.65 (d, 1H), 7.64 (d, 1H), 6,16 (d, 1H), 4.37 (m,1H), 4.23 (m, 1H), 4.38 (m, 1H), 4.56 (m, 1H), 2.63 (m, 1H), 2.10 (m,1H), 1.74 (s, 3H), 1.25-1.40 (m, 2H), 0.83 (t, J=7.46 Hz, 3H).

MS: (M−H)⁻=309, (M+35)⁺=345; (M+H)⁺=311, (M+Na)⁺=333.

EXAMPLE 204(±)-(2R,3R,5R)-2-Acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid Hydrochloride

204A(±)-(42R,3R,5R)-1-Benzyl-2-aminomethyl-3-t-butyldiphenylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound is prepared according to the method described inExample 1F, substituting(±)-(2R,3R,5R)-1-benzyl-2-formyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R)-1-benzyl-2-(1-oxo-3-ethyl)pentyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

MS: (M+H)⁺=435.

204B(±)-(2R,3R,5R)-1-Benzyl-2-acetamidomethyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound is prepared according to the method described inExample 1G, substituting(±)-(2R,3R,5R)-1-benzyl-2-aminomethyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of (±)-(2R,3R,5R,1′R)- and(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-amino-3-ethyl)pentyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (CDCl₃): δ 7.2-7.35 (m, 5H), 6.14 (br, 1H), 3.86 (dd, J=18 Hz,13.5 Hz, 2H), 3.67 (m, 1H), 3.60 (m, 1H), 3.49 (m, 1H), 3.28 (m, 1H),3.06 (m, 1H), 2.19 (m, 2H), 1.95 (s, 3H), 1.45 (s, 9H), 0.91 (s, 9H),0.07 (s, 6H).

MS: (M+H)⁺=477.

204C(±)-(2R,3R,5R)-1-Benzyl-2-acetamidomethyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 1H, substituting(±)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-t-butyldimethylsilyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester.

204D(±)-(2R,3R,5R)-1-Benzyl-2-acetamidomethyl-3-formyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 2A, substituting(±)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-hydroxymethyl-pyrrolidine-carboxylicacid t-butyl ester.

¹H NMR (CDCl₃): δ 9.70 (s, 1H), 7.22-7.36 (m, 5H), 5.82 (br, 1H), 3.83(dd, J=3.3 Hz, 13.5 Hz, 2H), 3.74 (m, 1H), 3.56 (d, J=9 Hz, 1H), 3.15(m, 1H), 2.73 (m, 1H), 2.36-2.10 (m, 2H), 1.98 (s, 3H), 1.45 (s, 9H).

MS: (M+H)⁺=361.

204E(±)-(2R,3R,5R)-1-Benzyl-2-acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 2B and 2C, substituting (±)-(2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-formyl-pyrrolidine-5-carboxylic acid t-butyl esterin place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-formyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (CDCl₃): δ 7.45-7.20 (m, 5H), 5.96 (br, 1H), 3.90-3.73 (m, 4H),3.71 (s, 3H), 3.52 (dd, J=9 Hz, 2 Hz, 1H), 3.13 (m, 1H), 2.84 (m, 1H),2.36 (m, 1H), 2.18 (m, 1H), 1.97 (s, 3H), 1.45 (s, 9H).

MS: (M+H)⁺=391.

204F(±)-(2R,3R,5R)-2-Acetamidomethyl-3-methoxycarbonyl-1-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 2D, substituting(±)2R,3R,5R)-1-benzyl-2-acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-1-benzyl-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (CDCl₃): δ 6.19 (br, 1H), 3.72 (m, 2H), 3.70 (s, 3H), 3.43 (m,1H), 3.28 (m, 1H), 2.74 (m, 1H), 2.44 (m, 1H), 2.21 (m, 1H), 2.00 (s,3H), 1.48 (s, 9H).

MS: (M+H)⁺=301.

204G(±)-(42R,3R,5R)-2-Acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicAcid Hydrochloride.

The title compound was prepared according to the method described inExample 2E substituting(±)-(2R,3R,5R)-2-acetamidomethyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxycarbonyl-pyrrolidine-5-carboxylicacid t-butyl ester.

¹H NMR (D₂O): δ 4.42 (t, J=8.25 Hz, 1H), 4.22 (m, 1H), 3.83 (m, 1H),3.75 (s, 3H), 3.70-3.60 (m, 2H), 3.26 (m, 11H), 2.78 (m, 1H), 2.43 (m,1H), 2.03 (s, 3H).

MS: (M+H)⁺=245.

EXAMPLES 205-213

The following title compounds were prepared according to the methodsdescribed in Examples 1-39 from the common intermediate prepared asdescribed in Example 204C.

EXAMPLE 205

(±)-(2R,3R,5R)-2-Acetamidomethyl-3-ethoxycarbonyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (D₂O) δ 4.30 (t, J=8.2 Hz, 1H), 4.21 (m, 3H), 3.62 (dd, J=2.4,3.4 Hz, 2H), 3.23 (m, 1H), 2.74 (m, 1H), 2.38 (m, 1H), 2.02 (s, 3H),1.26 (m, 3H).

MS: (M+H)⁺=259; (M−H)⁻=257.

EXAMPLE 206

(±)-(2R,3R,5R)-2-Acetamidomethyl-3-(imidazol-2-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride

¹H NMR (D₂O): δ 7.46 (s, 2H), 4.53 (dd, J=9.5 Hz, J=8.5 Hz, 1H), 4.28(m, 1H), 3.96 (m, 1H), 3.65 (m, 2H), 3.03 (dt, J=13.5 Hz, J=7.6 Hz, 1H),2.46 (m, 1H), 1.94 (s, 3H).

MS: (M+H)⁺=253, (M−H)⁻=251.

EXAMPLE 207

(±)-(2R,3S,5R)-2-Acetamidomethyl-3-vinyl-pyrrolidine-5-carboxylic AcidTrifluoroacetic Acid Salt

¹H NMR (D₂O) δ 5.74 (m, 1H), 5.24 (m, 2H), 4.20 (dd, J=1.7, 8.1 Hz, 1H),3.65 (m, 2H), 3.50 (m, 1H), 2.84 (m, 1H), 2.61 (m, 1H), 2.03 (s, 3H),1.95 (m, 1H).

MS: (M+H)⁺=213.

EXAMPLE 208

(±)-(2R,3R,5R)-2-Acetamidomethyl-3-(2,2-dimethyl-vinyl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (D₂O) δ 5.01 (br d, 1H), 4.18 (dd, J=2.1, 8.1 Hz, 1H), 3.53 (m,3H), 3.04 (m, 1H), 2.55 (m, 1H), 2.0 (s, 3H), 1.75 (m, 1H), 1.72 (s,3H), 1.67 (s, 3H).

MS: (M+H)⁺=241, (M+Na)⁺=263; (M−H)⁻=239.

EXAMPLE 209

(±)-(2R,3R,5R)-2-Acetamidomethyl-3-(N,N-dimethylcarbamoyl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (D2O) δ 4.60 (t, J=8.4 Hz, 1H), 4.23 (m, 1H), 3.56 (d, J=5.8 Hz,2H), 3.50 (m, 1H), 3.10 (s, 3H), 2.94 (s, 3H), 2.88 (m, 1H), 2.19 (m,1H), 2.00 (s, 3H).

MS: (M+H)⁺=258, (M−H)⁻=256.

EXAMPLE 210

(±)-(2R,3R,5R)-2-Acetamidomethyl-3-(N-N-methylcarbamoyl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (D₂O) 4.49 (t, J=8.5 Hz, 1H), 4.10 (m, 1H), 3.57 (d, J=5.8 Hz,2H), 3.03 (m, 1H), 2.76 (m, 1H), 2.74 (s, 3H), 2.29 (m, 1H), 2.00 (s,3H).

MS: (M+H)⁺=244.

EXAMPLE 211

(±)-(2R,3R,5R)-2-Acetamidomethyl-3-propionyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (D20) δ 4.24 (m, 2H), 3.55 (d, J=4.7 Hz, 1H), 3.40 (m, 1H), 2.85(m, 1H), 2.64 (m, 3H), 2.16 (m, 1H), 2.01 (s, 3H), 1.02 (t, J=7.1 Hz,3H).

MS: (M+H)⁺=243; (M−H)⁻=241.

EXAMPLE 212

(±)-(2R,3R,5R)-2-Acetamidomethyl-3-methoxymethyl-pyrrolidine-5-carboxylicAcid Hydrochloride

¹H NMR (D2O): δ 4.44 (t, J=6 Hz, 2H), 3.77 (m, 1H), 3.65-3.48 (m, 3H),3.35 (s, 3H), 2.64 (m, 1H), 2.56 (m, 1H), 2.03 (s, 3H), 2.00 (m, 1H).

MS: (M+H)⁺=231, (M−H)⁻=229.

EXAMPLE 213

(±)-(2R,3S,5R)-2-Acetamidomethyl-3-methyl-pyrrolidine-5-carboxylic AcidTrifluoroacetic Acid Salt

¹H NMR (D₂O) δ 4.30 (m, 1H), 3.64 (m, 1H), 3.48 (m, 1H), 3.20 (m, 1H),2.64 (m, 1H), 2.03 (s, 3H), 1.76 (m, 1H), 1.32 (br t, 1H), 1.12 (m, 4H).

MS: (M+H)⁺=201, (M+Na)⁺=223.

EXAMPLE 214(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

214A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-t-butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

To a solution of ethanethiol (0.047 mL, 0.63 mmol) in THF (2 mL) at 0°C. was added 2.5 M n-BuLi/hexane (0.248 mL, 0.62 mmol). The reactionmixture was stirred for 45 minutes and a solution of(±)-(2R,3S,5R,1′S)-1-t-butoxycarbonyl-2-(N-t-butoxycarbonylaziridinyl)-3-vinyl-pyrrolidine-carboxylicacid t-butyl ester (0.08 g, 0.182 mmole) in THF (0.5 mL) was addedfollowed by DMF (1.5 mL) and stirred at room temperature for 2 hours.The reaction was quenched with 1N NaHCO₃ (10 mL) and diluted with ethylacetate (20 mL). The organic layer was washed with water,and brine,dried over MgSO₄, filtered and concentrated in vacuo. The residue waspurified by chromatography on silica gel using 10% ethyl acetate/hexanesto provide the title compound (yield: 61 mg, 67%).

¹H NMR (d₆-DMSO) δ 6.74 (br d, 1H), 5.85 (m, 1H), 4.9-5.0 (m, 2H), 4.20(m, 1H), 3.95 (m, 1H), 3.75 (d, 1H), 2.8-3.0 (dd, 1H), 2.5 (m, 3H), 1.65(m, 1H), 1.32-1.45 (m, 27H), 1.17 (dt, 3H).

MS: (M−H)⁻=499; (M+H)⁺=501, (M+Na)⁺=523.

214B(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (58 mg, 0.116 mmole) was reacted with lithiumhexamethyldisilazide (1 M) (1.16 mL, 1.16 mmole) in THF (3 mL) at −78°C. After 0.5 hour at −78° C. and 1 hour at −40° C., the above reactionmixture was reacted with acetyl chloride (0.166 mL, 2.33 mmole) at −30°C. for 0.3 hours. The reaction was quenched with 1N NaHCO₃ (10 mL) andextracted with ethyl acetate (20 mL). The organic layer was washed withwater,and brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue was purified by chromatography on silica gel using 10% ethylacetate/hexanes to provide the title compound (yield. 28 mg, 44%).

¹H NMR (d₆-DMSO) δ 5.88 (m, 1H), 4.9-5.0 (m, 2H), 4.52 (m, 1H), 4.33 (m,1H), 4.1 (m, 1H), 2.78 (dd, 1H), 2.3-2.5 (m, 6H), 1.7 (m, 1H), 1.32-1.5(m, 27H), 1.11 (t, 3H).

MS: (M+H)⁺=543.

214C(±)-(2R,3R,5R,1′R)-2-(1-Acetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylthioethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 7 mg, 95%).

¹H NMR (d₆-DMSO) δ 8.15 (d, 1H), 5.72 (m, 1H), 5.05-5.2 (m, 2H), 4.2-4.4(m, 2H), 4.33 (m, 1H), 2.93 (m, 1H), 2.7-2.8 (2d, 1H), 2.3-2.6 (m, 3H),1.85-1.95 (m, 1H), 1.93 (s, 3H), 1.17 (t, J=7.46 Hz, 3H).

MS: (M+H)⁺=287.

EXAMPLE 215(±)-(2R,3S,5R,1′R,3′S)-2-(1-Acetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

215A (±)-(2R,3S,5R,1′R,3′S) and(±)-(2R,3S,5R,1′R,3′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (72 mg, 0.132 mmole) was reacted with 55%m-chloroperoxybenzoic acid (41 mg, 0.132 mmole) in CHCl₃ (1.5 mL) at−40° C. for 30 minutes. The reaction was concentrated in vacuo. Theresidue was purified by chromatography on silica gel using ethyl acetateto provide the title compounds (±)-(2R,3S,5R,1′R,3′S) isomer (yield: 14mg, 18.9%) and (±)-(2R,3S,5R,1′R,3′R) (yield: 45 mg, 60.7%).

(2R,3S,5R,1′R,3′S) ¹H NMR (d₆-DMSO) δ 5.88 (m, 1H), 4.9-5.0 (m, 2H),4.50 (m, 1H), 4.0-4.15 (m, 1H), 2.7-2.9 (m, 3H), 2.55 (m, 1H), 2.37 (s,3H), 1.7 (m, 1H), 1.32-1.5 (m, 27H), 1.12 (t, 3H).

MS: (M+H)⁺=559, (M+Na)+=581.

(2R,3S,5R,1′R,3′R) ¹H NMR (d₆-DMSO) δ 5.88 (m, 1H), 4.9-5.0 (m, 2H),4.50 (m, 1H), 4.03-4.15 (m, 1H), 3.2 (m, 1H), 3.1 (dd, 1H), 2.5-2.7 (m,2H), 2.38 (s, 3H), 1.75 (m, 1H), 1.32-1.5 (m, 27H), 1.12 (t, 3H).

MS: (M+H)⁺=559, (M+Na)+=581.

215B(±)-(2R,3S,5R,1′R,3′S)-2-(1-Acetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R,3′S)-1-t-butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid 1-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. ester (yield: 9 mg, 86%).

¹H NMR (d₆-DMSO) δ 8.39 (d, 1H), 5.72 (m, 1H), 5.15-5.2 (dd, 2H), 4.5(m, 1H), 4.37 (m, 1H), 3.65 (m, 1H), 2.85-3.04 (m, 3H), 2.6-2.85 (m,2H), 2.4 (m, 1H), 1.83-1.95 (m, 1H), 1.86 (s, 3H), 1.20 (t, J=7.46 Hz,3H).

MS: (M−H)⁻=301; (M+H)⁺=303, (M+Na)⁺=325.

EXAMPLE 216(±)-(2R,3S,5R,1′R,3′R)-2-(1-Acetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R,3′R)-1-t-butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of (±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 12 mg, 94%).

¹H NMR (d₆-DMSO) δ 8.39 (d, 1H), 5.72 (m, 1H), 5.15-5.2 (dd, 2H), 4.53(m, 1H), 4.41 (t, 1H), 3.65 (m, 1H), 3.2 (dd, 1H), 2.9-3.0 (m, 2H),2.65-2.9 (m, 2H), 2.4 (m, 1H), 1.83-1.95 (m, 1H), 1.83 (s, 3H), 1.20 (t,J=7.46 Hz, 3H).

MS: (M−H)−=301; (M+H)⁺=303, (M+Na)+=325.

EXAMPLE 217(±)-(2R,3S,5R,1′R)-2-(1-N-t-butoxycarbonylacetamido-2-ethylsulfonyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

217A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylsulfonyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R,3′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylsulfinyl)ethyl-3-vinyl-pyrrolidine-carboxylicacid t-butyl ester (25 mg, 0.0448 mmole) was reacted with 55%m-chloroperoxybenzoic acid (14 mg, 0.0448 mmole) in CHCl₃ (1.5 mL) at 0°C. for one hour. The reaction was concentrated in vacuo. The residue waspurified by chromatography on silica gel using 25% ethyl acetate/hexaneto provide the title compound (yield: 23.7 mg, 92%).

¹H NMR (d₆-DMSO) δ 5.88 (m, 1H), 4.85-5.0 (m, 2H), 4.38 (m, 1H), 4.15(m, 1H), 3.7 (m, 1H), 3.45 (dd, 1H), 2.9-3.2 (m, 3H), 2.5-2.7 (m, 1H),2.3-2.4 (m, 3H), 1.6-2.04 (m, 1H), 1.35-1.55 (m, 27H), 1.15 (t. 3H).

MS: (M+H)⁺=575.

217B(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethylsulfonyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-ethylsulfonyl)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 12 mg, 94%).

¹H NMR (d₆-DMSO) δ 8.34 (d, 1H), 5.72 (m, 1H), 5.05-5.25 (dd, 2H), 4.68(m, 1H), 4.39 (dd, 1H), 3.7 (2d, 1H), 3.48 (dd, 1H), 3.3-3.4 (dd, 2H),3.08 (q, 2H), 2.95 (m, 1H), 2.42 (m, 1H), 1.9 (m, 1H), 1.84 (s, 3H),1.23 (t, J=7.46 Hz, 3H).

MS: (M−H)⁻=317, (M+35)⁺=353; (M+H)⁺=319, (M+Na)⁺=341.

EXAMPLES 218, 220

The following title compounds were prepared in 3 steps according to themethods described in Example 214.

EXAMPLE 218(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

218A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 214A, substituting isopropylthiol in place of ethanethiol(yield: 22 mg, 62%).

¹H NMR (d₆-DMSO) δ 6.73 (d, 1H), 5.85 (m, 1H), 4.9-5.0 (m, 2H), 4.18 (m,1H), 3.95 (m, 1H), 3.75 (br d, 1H), 2.8-3.0 (m, 2H), 1.65 (m, 1H),1.32-1.45 (m, 27H), 1.18 (dd, 6H).

MS: (M−H)−=513; (M+H)⁺=515, (M+Na)+=537.

218B(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-(N-t-butoxycarbonyl-N-acetamido)-2-isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 214B, substituting(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-isoproylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 12 mg, 50%).

¹H NMR (d₆-DMSO) δ 5.86 (m, 1H), 4.88-5.0 (m, 2H), 4.54 (m, 1H), 4.33(m, 1H), 4.13 (d, 1H), 3.05 (m, 1H), 2.73-2.84 (m, 2H), 2.38 (br s, 3H),1.72 (m, 1H), 1.32-1.5 (m, 27H), 1.14 (dd, 6H).

MS: (M+H)⁺=557, (M+Na)+=579.

218C(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 15B, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-isopropylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield 8 mg, 97%).

¹H NMR (d₆-DMSO) δ 8.14 (d, 1H), 5.72 (m, 1H), 5.05-5.2 (dd, 2H),4.2-4.4 (m, 2H), 3.68 (dd, 1H), 2.93 (m, 2H), 2.74 (dd, 1H), 2.58 (dd,1H), 1.93 (m, 1H), 1.87 (s, 3H), 1.2 (t, 6H).

MS: (M−H)−=299; (M+H)⁺=301, (M+Na)+=323.

EXAMPLE 219(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-phenylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride

219A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-amino-2-phenylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′S)-1-t-Butoxycarbonyl-2-aziridinyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (20.3 mg, 0.06 mmole) was reacted with thephenylthiol (19.9 mg, 0.18 mmol) and triethylamine (0.047 mL, 0.34 mmol)in MeOH (0.06 mL) at ambient temperature for 3.5 hours. The reactionsolution was concentrated in vacuo. The residue was purified bypreparative thin layer chromatography on silica gel using ethylacetate/methanol/ammonium hydroxide, 99/0.05/0.05, to provide the titlecompound (yield: 20.7 mg, 77%).

¹H NMR (d₆DMSO) δ 7.31 (m, 4H), 7.17 (m, 1H), 5.87 (m, 1H), 5.03 (d,J=17 Hz, 0.4H), 5.01 (d, J=17 Hz, 0.6H), 4.91 (d, J=11H, 0.4H), 4.90 (d,J=11 Hz, 0.6H), 4.15 (m, 1H), 3.82 (m, 0.6H), 3.76 (m, 0.4H), 3.39 (m,1H), 2.92 (m, 2H), 2.55 (m, 1H), 1.64 (m, 2H), 1.42 (s, 5.4H), 1.37 (s,3.6H), 1.34 (s, 5.4H), 1.22 (s, 3.6H).

MS: (M+H)⁺=449, (M+Na)⁺=471.

219B(±)-(42R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-phenylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-amino-2-phenylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylic acid t-butyl ester(17.2 mg, 0.04 mmole) was reacted with the acetic anhydride (0.011 mL,0.11 mmol) and triethylamine (0.032 mL, 0.23 mmol) in CH₂Cl₂ (0.3 mL) atrt for 4.25 hours. The reaction solution was concentrated in vacuo. Theresidue was purified by preparative thin layer chromatography on silicagel using 5% methanol/dichloromethane to provide the title compound.

¹H NMR (d₆-DMSO) δ 7.75 (d, J=9 Hz, 0.6H), 7.73 (d, J=9 Hz, 0.4H), 7.32(m, 4H), 7.19 (m, 1H), 5.87 (m, 1H), 5.04 (d, J=17 Hz, 0.4H), 5.00 (d,J=17 Hz, 0.6H), 4.95 (d, J=10 Hz, 0.6H), 4.93 (d, J=10 Hz, 0.4H), 4.59(m, 0.4H), 4.45 (m, 0.6H), 3.99 (dd, J=10 Hz, 2 Hz, 0.6H), 3.94 (dd,J=10 Hz, 2.5 Hz, 0.4H), 3.84 (m, 0.6H), 3.77 (m, 0.4H), 3.07 (dd, 13 Hz,5 Hz, 0.6H), 2.95 (m, 1.8H), 2.83 (br t, J=8 Hz, 0.6H), 2.48 (m, 1H),1.84 (s, 1.2H), 1.81 (s, 1.8H), 1.68 (m, 1H), 1.41 (s, 5.4H), 1.36 (s,3.6H), 1.34 (s, 5.4H), 1.26 (s, 3.6H).

MS: (M−H)⁻=489, (M+35)⁻; (M+H)⁺=490, (M+Na)⁺=513.

219C(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-phenylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Hydrochloride

The title compound was prepared according to the method described inExample 1K, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-phenylthiothyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-ethyl)pentyl-3-methoxymethyl)-pyrrolidine-5-carboxylicadd t-butyl ester (yield: 14.6 mg, 100%.)

¹H NMR (d₄-methanol) δ 7.43 (m, 2H), 7.31 (m, 3H), 5.75 (ddd, J=17 Hz,10 Hz, 8 Hz, 1H), 5.32 (br d, J=17 Hz, 1H), 5.19 (dd, J=10 Hz, 1.4 Hz,1H), 4.58 (m, 2H), 3.89 (dd, J=10 Hz, 3 Hz, 1H), 3.19 (dd, J=14 Hz, 6Hz, 1H), 3.09 (dd, J=14 Hz, 9 Hz, 1H), 3.04 (m, 1H), 2.57 (dt, J=13 Hz,7 Hz, 1H), 2.04 (s, 3H), 2.03 (m, 1H).

MS: (M−H)⁻=333; (M+H)⁺=335, (M+Na)⁺=357.

EXAMPLE 220(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

220A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 214A, substituting benzylmercaptan in place of ethanethiol(yield: 28 mg, 72%).

¹H NMR (d₆-DMSO) δ 7.2-7.35 (m, 5H), 6.80 (br d, 1H), 5.84 (m, 1H),4.86-4.96 (m, 2H), 4.25 (m, 1H), 3.95 (m, 1H), 3.7-3.8 (m, 3H),2.76-2.94 (m, 1H), 2.35-2.45 (m, 2H), 1.65 (m, 1H), 1.32-1.45 (m, 27H).

MS: (M−H)−=561; (M+H)⁺=563, (M+Na)+=585.

220B(±)-(42R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-(N-t-butoxycarbonyl-acetamido)-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 21 4B, substituting(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-N-t-butoxycarbonylamino-2-ethylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 3.3 mg, 61%).

¹H NMR (d₆-DMSO) δ 7.2-7.35 (m, 5H), 5.84 (m, 1H), 4.86-4.96 (m, 2H),4.55 (m, 1H), 4.32 (d, 1H), 4.05 (d, 1H), 3.56-3.65 (m, 2H), 2.9 (m,1H), 2.3-2.65 (m, 3H), 2.42 (s, 3H), 1.76 (d, 1H), 1.25-1.55 (m, 27H).

MS: (M+H)⁺=605, (M+Na)+=627.

220C(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-N-t-butoxycarbonylacetamido-2-benzylthio)ethyl-3-vinyl-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2.2 mg, 95%).

¹H NMR (d₆-DMSO) δ 8.18 (d, 1H), 7.2-7.32 (m, 5H), 5.68 (m, 1H),5.02-5.2 (m, 2H), 4.3-4.45 (m, 2H), 3.76 (s, 2H), 3.68 (dd, 1H), 2.92(m, 1H), 2.62 (dd, 1H), 2.32-2.55 (m, 2H), 1.85-1.95 (m, 1H), 1.89 (s,3H).

MS: (M−H)⁻=347: (M+H)⁺=349, (M+Na)⁺=371.

EXAMPLE 221

(±)-(2R,3S5R,1′R)-2-(1-Acetamido-2-(4-pyridinethio)ethyl-3-vinyl-pyrrolidine-5-carboxylicAcid Dihydrochloride

The title compound was prepared according to the method of Example219A-C substituting 4-thiopyridine for thiophenol as the reagent inExample 219A.

¹H NMR (d₄-methanol) δ 8.57 (d, J=7 Hz 2H), 7 97 (d, J=7 Hz, 2H), 5.85(ddd, J=17 Hz, 10 Hz, 9 Hz, 1H), 5.40 (br d, J=17 Hz, 1H), 5.25 (dd,J=17 Hz, 10 Hz, 1H), 4.67 (dt, J=10 Hz, 4 Hz, 1H), 4.47 (dd, J=10 Hz, 8Hz, 1H), 4.01 (dd, J=10 Hz, 4 Hz, 1H), 3.68 (dd, J=14 Hz, 5 Hz, 1H),3.45 (dd, J=14 Hz, 10 Hz, 1H), 3.16 (m, 1H), 2.65 (dt, J=14 Hz, 7 Hz,1H), 2.07 (m, 1H), 2.04 (s, 3H).

MS: (M−H)⁻=334; (M+H)⁺=336, (M+Na)⁺=358.

EXAMPLE 222

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propyn-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

Thionyl chloride (1.49 mL, 20.5 mmol) was reacted with ethanol (25 mL)at 0C for 10 minutes.(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt (815 mg, 2.05 mmol) in ethanol (50 mL)was added to the above solution and reacted at room temperature for 17hours. The reaction was concentrated in vacuo and the residue waspurified by chromatography on silica gel with 90/10/0.5dichloromethane/methanol/ammonium hydroxide to provide the titlecompound as a white solid (yield: 462 mg, 72%).

¹H NMR (DMSO-d₆) δ 7.49 (d, J=9.8 Hz, 1H), 5.31 (m, 2H), 4.11 (m, 2H),3.72 (t, J=7.7 Hz, 1H), 3.69 (m, 1H), 3.42 (m, 1H), 3.07 (m, 1H), 2.85(m, 1H), 2.22 (m, 1H), 1.76 (s, 3H), 1.54 (d, J=5.6 Hz, 3H), 1.45 (m,1H), 1.39 (m, 1H), 1.21 (m, 1H), 1.19 (t, J=7.0 Hz, 3H), 0.83 (t, J=7.3Hz, 3H).

MS: (M+H)⁺=313, (M+Na)⁺=335, (M−H)⁻=311.

EXAMPLE 223

(±)-(2R,3R,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

The title compound is prepared according to the method described inExample 222, substituting(±)-(2R,3R,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt in place of(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylictrifluoroacetic acid salt (yield: 32 mg, 52%).

¹H NMR (d₆-DMSO) δ 7.6 (br s, 1H), 6.1 (br s, 1H), 4.08 (q, J=7.12 Hz,2H), 3.78 (m, 1H), 3.65 (m, 1H), 3.55 (m, 1H), 3.45 (m, 1H), 3.25 (m,1H), 3.45 (m, 1H), 1.72 (s, 3H), 1.45 (m, 1H), 1.2 (m, 1H), 1.16 (t,J=7.12 Hz, 3H), 0.82 (t, J=7.46 Hz, 3H).

MS: (M−H)⁻=337, (M+35)⁺=373; (M+H)⁺=339, (M+Na)⁺=361.

EXAMPLE 224

(±)42R,3S,5R,1′S,3′S)-2-(1-Acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

The title compound is prepared according to the method described inExample 222, substituting(±)-(2R,3S,5R,1′S,3′S)-2-(1-acetamido-2-(N-isopropyl-N-methylamino-N-oxide))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt in place of(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt (yield: 25 mg, 34%).

¹H NMR (MeOD-d₃) δ 5.51-5.43 (m, 1H), 5.34-5.27 (m, 1H), 4.36-4.30 (m,1H), 4.18 (q, J=7.1 Hz, 2H), 3.88 (dd, J=6.8, 8.8 Hz, 1H), 3.82-3.67 (m,2H), 3.49-3.42 (m, 1H), 3.34 (s, 3H), 3.14-2.96 (m, 1H), 2.42-2.33 (m,1H), 1.92 (s, 3H), 1.64-1.52 (m, 1H), 1.63 (dd, J=1.7, 6.8 Hz, 3H),1.41-1.24 (m, 1H), 1.39 (d, J=6.4 Hz, 3H), 1.31 (d, J=6.4 Hz, 3H), 1.26(t, J=7.1 Hz, 3H).

MS: (M+H)⁺=356, (M+Na)⁺=378, (M−H)⁻=354, (M+35)⁺=390.

EXAMPLE 225

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

The title compound is prepared according to the method described inExample 222, substituting(±)-(2R,3S,5R,1′S)-2-(1-acetamidomethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt in place of(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt (yield: 838 mg, 94%).

1H NMR (CDCl₃): δ 5.50 (m, 1H), 5.41 (m, 1H), 5.28 (m, 1H), 4.21 (q,J=7.5 Hz, 2H), 4.06 (m, 1H), 3.87 (t, J=7.5 Hz, 1H), 3.10 (m, 1H), 2.97(m, 1H), 2.39 (m, 1H), 1.97 (s, 3H), 1.66 (dd, 3H), 1.60 (m, 1H), 1.40(m, 2H), 0.94 (d, J=7.5 Hz, 3H), 0.93 (d, J=7.5 Hz, 3H).

MS: (M+H)⁺=311.

EXAMPLE 226

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-methylbutyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

The title compound is prepared according to the method described inExample 222, substituting(±)-(2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(cis-2-chloro-vin-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt in place of(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt (yield: 28 mg, 46%).

¹H NMR (CDCl₃): δ 6.05 (d, J=7.5 Hz, 1H), 5.90 (dd, J1=9 Hz, J2=6 Hz,1H), 5.31 (d, J=9 Hz, 1H), 4.19 (q, J=7.5 Hz, 2H), 4.06 (m, 1H), 3.82(t, J=7.5 Hz, 1H), 3.17 (m, 2H), 2.45 (m, 1H), 1.98 (s, 3H), 1.67 (m,1H), 1.60 (m, 1H), 1.37 (m, 2H), 1.27 (t, J=7.5 Hz, 3H), 0.91 (d, J=7.5Hz, 3H), 0.89 (d, J=7.5 Hz, 3H).

MS: (M+H)⁺=331.

EXAMPLE 227 Intentionally Blank EXAMPLE 228

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(2,2-difluoro-vinyl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

The title compound is prepared according to the method described inExample 222, substituting(±)2R,3S,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(2,2-difluoro-vinyl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt in place of(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt (yield: 28 mg, 57%).

¹H NMR (CDCl₃): δ 4.22 (q, J=7.5 Hz, 2H), 4.14 (m, 1H), 4.03 (m, 1H),3.29 (br, 1H), 2.85 (m, 1H), 2.52 (m, 1H), 2.01 (s, 3H), 1.77 (m, 2H),1.64 (m, 2H), 1.49 (m, 1H), 1.38 (m, 1H), 1.29 (t, J=7.5 Hz, 3H), 0.93(d, J=7.5 Hz, 3H), 0.90 (d, J=7.5 Hz, 3H).

MS: (M+H)⁺=333.

EXAMPLE 229

(±)-(2R,3R,5R,1′S)-2-(1-Acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

The title compound is prepared according to the method described inExample 222, substituting(±)-(2R,3R,5R,1′S)-2-(1-acetamido-3-methyl)butyl-3-(pyrazol-3-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid shaft in place of(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt (yield: 48 mg, 75-5%).

¹H NMR (CDCl₃): δ 7.49 (d, 1H), 7.26 (s, 1H), 6.18 (d, 1H), 4.18 (q,J=7.5 Hz, 2H), 4.12 (m, 1H), 3.91 (t, J=7.5 Hz, 1H), 3.51 (t, J=7.5 Hz,1H), 3.40 (q, J=9 Hz, 1H), 2.64 (m, 1H), 2.00 (m, 1H), 1.82 (s, 3H),1.75 (m, 1H), 1.36 (m, 1H), 1.26 (t, J=9 Hz, 3H), 0.855 (d, 3H), 0.84(d, 3H).

MS: (M+H)⁺=337.

EXAMPLE 230(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

230A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 41B, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester for (±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester to provide the title compound (yield: 0.021 g, 51%).

MS: (M+H)⁺=469, (M+Na)⁺=491, (2M+Na)⁺=959, (M−H)⁻=467.

230B(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0039 g, 100%).

¹H NMR (DMSO-d₆) δ 7.52 (d, J=10.3 Hz, 1H), 5.45 (m, 1H), 5.28 (m, 1H),4.32 (m, 2H), 3.68 (t, J=8.8 Hz, 1H), 3.16 (quint., J=8.5 Hz, 1H), 2.41(dt, J=13.2, 8.3 Hz, 1H), 1.81 (s, 3H), 1.59 (m, 1H), 1.53 (dd, J=6.8,1.5 Hz, 3H), 1.52-1.42 (m, 3H), 1.30 (m, 1H), 0.86 (t, J=7.3 Hz, 3H),0.83 (t, J=7.3 Hz, 3H).

MS: (M+H)⁺=313, (M+Na)⁺=335, (M−H)⁻=311, (2M−H)⁻=623.

EXAMPLE 231(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

231A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 41B, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester for (±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester and methylmagnesium bromide for ethylmagnesiumbromide to provide the title compound (yield: 0.0285 g, 45%).

MS: (M+H)⁺=469, (M+Na)⁺=491.

231B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0040 g, 100%).

¹H NMR (DMSO-d₆) δ 9.25 (bs, 1H), 8.75 (bs, 1H), 7.54 (d, J=10.3 Hz,1H), 5.45 (m, 1H), 5.29 (m, 11H), 4.37 (bt, J=8.3 Hz, 1H), 4.22 (t,J=9.7 Hz, 1H), 3.62 (t, J=8.8 Hz, 1H), 3.12 (quint, J=8.5 Hz, 1H), 2.41(dt, J=12.7, 7.8 Hz, 1H), 1.78 (s, 3H), 1.59 (m, 1H), 1.53 (dd, J=6.8,2.0 Hz, 3H), 1.4-1.25 (m, 4H), 1.17 (s, 3H), 0.81 (t, J=6.5 Hz, 3H).

MS: (M+H)⁺=313, (M+Na)⁺=335, (M−H)⁻=311, (2M−H)⁻=623.

EXAMPLE 232(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

232A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)pent-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 41B, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester for (±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl2-(1-acetamido-1-formyl)methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester to provide the title compound (yield: 0.0222 g, 33%).

MS: (M+H)⁺=483, (M+Na)⁺=505, (M−H)⁻=481.

232B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0035 g, 100%).

¹H NMR (DMSO-d₆) δ 9.1 (bs, 1H), 8.75 (bs, 1H), 7.53 (d, J=9.8 Hz, 1H),5.44 (m, 1H), 5.28 (m, 1H), 4.35-4.25 (m, 2H), 3.67 (m, 1H), 3.16(quint., J=8.5 Hz, 1H), 2.41 (dt, J=12.8, 7.9 Hz, 1H), 1.81 (s, 3H),1.60 (m, 1H), 1.53 (dd, J=6.7, 1.8 Hz, 3H), 1.46 (m, 2H), 1.4-1.20 (m,4H), 0.86 (t, J=7.3 Hz, 3H), 0.82 (t, J=6.7 Hz, 3H).

MS: (M+H)⁺=327, (M−H)⁻=325, (M+CF₃COOH)⁻=439, (2M−H)⁻=651.

EXAMPLE 233

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-propyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 232 substituting propyl magnesium bromide for ethyl magnesiumbromide.

¹H NMR (DMSO-d₆): δ 0.81 (t, 3H), 0.91 (t, 3H), 1.24-1.49 (m, 8H), 1.54(dd, 3H), 1.60 (m, 1H), 1.81 (s, 3H), 2.41 (m, 1H), 3.15 (m, 1H), 3.69(t, 1H), 4.28 (t, 1H), 4.35 (t, 1H), 5.17 (br s, 1H), 5.28 (td, 1H),5.45 (dq, 1H), 7.54 (d, 1H), 8.80 (br s, 1H), 9.12 (br s, 1H).

MS: (M+H)⁺=341.

EXAMPLE 234(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

234A(0)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-ethyl-2-(methylthio)methyloxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester was reacted with dimethylsulfoxide and aceticanhydride according to the method of Marshall, J. A. in J. Org. Chem.1979, vol. 44, p 2994 to provide the title compound.

234A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-ethyl-2-(methylthio)methyloxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester is reacted with Raney Nickel according to theprocedure of Marshall, J. A. in J. Org. Chem. 1979, vol. 44, p 2994 toprovide the title compound.

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound is prepared according to the method described inExample 41 C, substituting (±)-(2R,3S,5R,1′R,2′S1-t-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-methoxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester.

EXAMPLE 235

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethyl-2-methoxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound is prepared according to the method described inExample 234 substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-ethyl-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in 234A.

EXAMPLE 236(±)-(42R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

236A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-((1-ethoxy)ethyloxymethyl)-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-oxo)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (50 mg, 0.11 mmole) was reacted with(ethoxyethyloxymethyl)tributylstannane (260 mg, 0.66 mmole) according tothe method of Still, W. C. (J. Am. Chem. Soc., 100, 1481 (1978)) toprovide the title compound (yield: 26.8 mg, 43.8%).

¹H NMR (CDCl₃): δ 0.89 (t, 3H), 1.19 (m, 3H), 1.29 (dd, 3H), 1.45 (s,9H), 1.46 (s, 9H), 1.52-1.73 (m, 8H), 1.99 (s, 3H), 2.44 (m, 1H),3.24-3.74 (m, 5H), 3.91-4.22 (m, 3H), 4.49 (m, 1H), 4.62 (m, 1H), 5.37(m, 1H), 5.64 (m, 1H), 5.97-6.41 (m, 1H).

MS: (M+H)+=557.

236B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxymethyl-2-hydroxyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-(1-ethoxy-2-ethoxymethyl)-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester (13.5 mg, 0.024 mmol) was dissolved in THF (1 mL) andtreated with 0.5 N HCl (1 mL) at room temperature for 1 hr. The solventswere removed and the resulting white solid was reacted withtrifluoroacetic acid (0.8 mL) in dichloromethane (0.2 mL) at roomtemperature for 6 hours. The reaction was concentrated in vacuoovernight to provide the title compound (yield: 10.7 mg) as a off whitesolid.

¹H NMR (DMSO-d₆): δ 0.81 (t, 3H), 1.24-1.38 (m, 4H), 1.52 (dd, 3H), 1.62(m, 1H), 1.78 (s, 3H), 2.41 (m, 1H), 3.11 (m, 1H), 3.51 (q_(AB), 2H),3.77 (t, 1H), 4.23 (t, 1H), 4.40 (m, 1H), 5.27 (t, 1H), 5.45 (m, 1H),7.55 (d, 1H), 8.87 (br s, 1H), 9.26 (br s, 1H).

MS: (M+H)⁺=329.

EXAMPLE 237(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-allyloxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

237A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-21-acetamido-2-hydroxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester was reacted according to the method described inExample 84A substituting allyl iodide for methyl iodide (yield: 28 mg,80%).

MS: (M+H)⁺=479, (M−H)⁻=477.

237B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-allyloxy-2-vinyl)ethyl-3-(cis-propen-1-yl-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. (yield: 4 mg, 1 00%).

¹H NMR (DMSO-d6) δ 7.98 (d, J=7.8 Hz, 1H), 5.90 (m, 1H), 5.55 (m, 1H),5.48 (m, 1H), 5.32 (m, 2H), 5.26 (m, 2H), 5.16 (m, 1H), 4.28 (m, 2H),3.96 (m, 1H), 3.79 (m, 1H), 3.73 (m, 1H), 3.66 (m, 1H), 3.26 (m, 1H),2.40 (m, 1H), 1.81 (s, 3H), 1.70 (m, 1H), 1.64 (dd, J=6.9, 1.5 Hz, 3H).

MS: (M+H)⁺=323, (M−H)⁻=321.

EXAMPLE 238(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

238A (±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido1-(2,5-dihydrofuran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamide-2-allyloxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (21 mg, 0.044 mmole) prepared according to theprocedure of Example 237A was reacted withbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride [Grubb'scatalyst] (7.5 mg, 0.009 mmole) in methylene chloride (5 mL) at 25° C.for 2 hours under a nitrogen atmosphere. The reaction was concentratedin vacuo and the resulting residue purified by chromatography on silicagel using 75% ethyl acetate/hexanes to provide the title compound(yield: 18 mg, 90%).

MS: (M+H)⁺=451, (M−H)⁻=449.

238B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-1-(2,5-dihydrofuran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. (yield: 7 mg, 100%).

¹H NMR (DMSO-d₆) δ 8.09 (d, J=8.8 Hz, 1H), 6.10 (m, 1H), 5.87 (m, 1H),5.50 (m, 1H), 5.27 (m, 1H), 4.68 (m, 2H), 4.58 (m, 1H), 4.33 (m, 1H),4.06 (m, 1H), 3.68 (m, 1H), 3.18 (m, 1H), 2.40 (m, 1H), 1.85 (s, 3H),1.68 (m, 1H), 1.60 (dd, J=6.8, 1.5 Hz, 3H),

MS: (M+H)⁺=295, (M−H)⁻=293.

EXAMPLE 239(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-allyloxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

239A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-allyloxy-2-allylethyl-1-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester was reacted according to the method described inExample 84A substituting allyl iodide for methyl iodide iodide (yield:19 mg, 36%).

MS: (M+H)⁺=493, (M−H)⁻=491.

239B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-allyloxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-Acetamido-2-allyloxy-2-allyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. (yield: 5.7 mg, 100%).

¹H NMR (DMSO-d₆) δ 8.06 (dd, J=8.8 Hz, 1H), 6.92 (m, 1H), 6.77 (m, 1H),5.50 (m, 1H), 5.29 (m, 2H), 5.17 (m, 1H), 5.05 (m, 2H), 4.27 (m, 2H),4.10 (dd, J=12.2, 5.4 Hz, 1H), 3.83 (m, 1H), 3.78 (m, 1H), 3.40 (m, 1H),3.20 (m, 1H), 2.46 (m, 1H), 2.38 (m, 1H), 2.20 (m, 1H), 1.88 (s, 3H),1.69 (m, 1H), 1.63 (dd, J=6.8, 1.5 Hz, 3H).

MS: (M+H)⁺=337, (M+Na)⁺=359, (M−H)⁻=335.

EXAMPLE 240(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

240A(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-allyloxy-2-allyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (11.5 mg, 0.023 mmole) prepared according to theprocedure of Example 239A was reacted withbis(tricyclohexylphosphine)benzylidine ruthenium(IV) dichloride [Grubb'scatalyst] (3.8 mg, 0.005 mmole) in methylene chloride (3 mL) at 25° C.for 3 hours under a nitrogen atmosphere. The reaction was concentratedin vacuo and the resulting residue purified by chromatography on silicagel using 75% ethyl acetate/hexanes to provide the title compound(yield: 5.7 mg, 53%).

MS: (M+H)⁺=465, (M+Na)+=487, (M−H)⁻=463.

240B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))methyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester. (yield: 5.9 mg, 100%).

¹H NMR (DMSO-d6) δ 8.04 (d, J=8.8 Hz, 1H), 5.77 (m, 2H), 5.50 (m, 1H),5.25 (m, 1H), 4.21 (m, 2H), 4.14 (m, 1H), 4.04 (m, 1H), 3.81 (m, 1H),3.40 (m, 1H), 3.23 (m, 1H), 2.41 (m, 1H), 2.09 (m, 1H), 1.88 (s, 3H),1.83 (m, 1H), 1.70 (m, 1H), 1.63 (d, J=6.8 Hz, 3H).

MS: (M+H)⁺=309, (M+Na)⁺=331, (M−H)⁻=307.

The following compounds were synthesized according to the methodspreviously described in Examples 1-240

EXAMPLE 241

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-1-(3,6-dihydro-2-H-pyran-2-yl))propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.90 (d, 9.1 Hz, 1H), 5.79 (m, 2H), 5.48 (m, 1H),5.23 (m, 1H), 4.43 (m, 1H), 4.24 (m, 2H), 4.17 (m, 2H), 3.73 (m, 1H),3.64 (m, 1H), 3.19 (m, 1H), 2.42 (m, 1H), 2.02 (m, 1H), 1.85 (s, 3H),1.78 (m, 1H), 1.75 (m, 1H), 1.56 (dd, J=7.5, 1.5 Hz, 3H).

MS: (M+H)⁺=309, (M+Na)⁺=331, (M−H)⁻=307.

EXAMPLE 242

(±)-(2R,3S,5R,1′S,2′RS)-2-(1-Acetamido-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO) δ 7.7 (d, J=9.8 Hz, 1H), 5.61 (m, 1H), 5.19 (dt, J=1.8,11.0 Hz, 1H), 4.33 (dd, J=6.7, 10.3 Hz, 1H), 3.81 (m, 1H), 3.70 (dd,1.8, 10.3 Hz, 1H), 3.54 (q, J=6.1 Hz, 1H), 3.10 (m, 1H), 2.35 (dt,J=12.8, 6.8 Hz, 1H), 1.90 (s, 3H), 1.7 (m, 1H), 1.59 (dd, J=0.7, 7.3 Hz,3H), 1.4 (m, 3H), 1.2 (m, 2H), 0.90 (t, J=6.7 Hz, 3H).

MS: (M+H)⁺=299.

EXAMPLE 243

(±)-(2R,3S,5R,1′S,2′RS)-2-(1-Acetamido-2-hydroxy-3-ethoxycarbonyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO) δ 7.75 (m, 1H), 5.60 (m, 1H), 5.29 (m, 1H), 4.55-4.25 (m,3H), 4.15-4.0 (m, 3H), 3.9-3.6 (m, 3H), 3.15 (m, 1H), 2.45-2.3 (m, 2H),1.9 (s, 3H), 1.8-1.5 (m, 5H), 1.2 (m, 3H).

MS: (M+H)⁺=343.

EXAMPLE 244

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) d 7.91 (d, J=8.05 Hz, 1H), 5.50 (m, 2H), 5.30 (m, 3H),4.27 (m, 1H), 4.23 (m, 1H), 3.75 (m, 1H), 3.48 (m, 1H), 3.23 (m, 1H),3.15 (s, 3H), 2.40 (m, 1H), 1-80 (s, 3H), 1.68 (m, 1H), 1.64 (dd,J=1.83, 7.32 Hz, 3H).

MS: (M+H)⁺=297, (M−H)⁻=295.

EXAMPLE 245

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy-2-vinyl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) d 7.90 (d, J=7.85 Hz, 1H), 5.57 (m, 2H), 5.48 (m, 3H),4.27 (m, 1H), 4.22 (m, 1H), 3.77 (m, 1H), 3.60 (m, 1H), 3.46 (m, 1H),3.23 (m, 2H), 2.39 (m, 1H), 1.80 (s, 3H), 1.70 (m, 1H), 1.64 (dd,J=1.47, 6.73 Hz, 3H), 1.12 (t, J=6.83 Hz, 3H).

MS: (M+H)⁺=311, (M−H)⁻=309.

EXAMPLE 246

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.69 (d, J=9.75 Hz 1H), 5.47 (m, 1H), 5.28 (m, 1H),5.03 (m, 1H), 4.86 (m, 1H), 4.40 (m, 1H), 4.30 (m, 1H), 4.18 (m, 1H),3.97 (m, 1H), 3.68 (m, 1H), 3.21 (m, 1H), 2.43 (m, 1H), 1.82 (m, 1H),1.73 (s, 3H), 1.64 (s, 3H), 1.59 (m, 3H).

MS: (M+H)⁺=297, (M−H)⁻=295.

EXAMPLE 247

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2-hydroxy-2-(propeny-2-yl)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.65 (d, J=9.80 HZ, 1H), 5.48 (m, 1H), 5.23 (m, 1H),4.99 (s, 1H), 4.88 (s, 1H), 4.46 (m, 1H), 4.30 (m, 1H), 4.19 (m, 1H),3.55 (m, 1H), 3.22 (m, 1H), 2.44 (m, 1H), 1.78 (s, 3H), 1.75 (m, 1H),1.65 (s, 3H), 1.58 (dd, J=1.23, 6.70 HZ, 3H).

MS: (M+H)⁺=297, (M−H)⁻=295.

EXAMPLE 248

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-propeny-2-yl))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) d 7,77 (d, J=9.8 Hz, 1H), 5.49 (m, 1H), 5.25 (m ,1H),5.07 (m, 1H), 4.94 (m, 1H), 4.32 (m, 1H), 4.25 (m, 1H), 3.75 (m, 1H),3.48 (m, 1H), 3.25 (m, 1H), 3.08 (s, 3H), 2.40 (m, 1H), 1.77 (s, 3H),1.68 (m, 1H), 1.64 (dd, J=1.22, 6.71 Hz, 3H), 1.56 (s, 3H).

MS: (M+H)⁺=311, (M−H)⁻=309.

EXAMPLE 249

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.62 (d, J=9.21 Hz, 1H), 5.58 (m, 1H), 5.28 (m, 1H),4.37 (m, 1H), 3.98 (m, 1H), 3.57 (m, 1H), 3.10 (m, 1H), 2.45 (m, 1H),1.92 (s, 3H), 1.76 (m, 1H), 1.62 (dd, J=1.83, 6.72 Hz, 3H), 1.24 (m,5H), 0.84 (t, J=7.61 Hz, 3H), 0.77 (t, J=7.61 Hz, 3H).

MS: (M+H)⁺=297, (M−H)⁻=295.

EXAMPLE 250

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.76 (d, J=9.2 Hz, 1H), 5.46 (m, 1H), 5.29 (m, 1H),4.23 (m, 1H), 3.63 (m, 1H), 3.15 (m, 1H), 3.01 (m, 1H), 2.38 (m, 1H),1.87 (s, 3H), 1.71 (m, 1H), 1.60 (m, 3H), 1.36 (m, 1H), 1.20 (m, 4H),0.83 (t, J=7.3 Hz, 6H).

MS: (M+H)⁺=297, (M−H)⁻=295.

EXAMPLE 251

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester and(±)-(2S,3R,5S,1′R)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ethyl ester (100 mg) was chromatographed in one injection on achiral HPLC column of dimensions 5×30 cm. The column was packed withChiralpak AD chiral stationary phase packing from Chiral Technologies.The mobile phase consisted of 1:9 ethanol:hexanes at a flow rate of 117mL/min. Two peaks were observed at (24-36) minutes (−)-(2R,3S,5R,1′S)(yield: 45 mg) and at (66-96) min (±)-(2S,3R,5S,1′R) (yield: 45 mg).

(−)-(2R,3S,5R,1′S) [α]_(D)=−26° (c=0.78, dichloromethane).

EXAMPLE 252(−)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylateAmmonium Salt

(−)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ethyl ester (4.9 mg, 0.0157 mmole) prepared according to theprocedure of Example 251 was reacted with lithium hydroxide (0.75 mg,0.0314 mmole) in a mixture of methanol (0.75 mL) and water (0.25 mL) at0° C. for 7 hours. Then 0.1 N aqueous Hydrochloric acid (1 mL) wasadded, the reaction was concentrated in vacuo and the resulting residuepurified by ion exchange chromatography on Aldrich Dowex 50WX8-400strongly acidic resin. The residue was placed on the column and washedwith water (5 mL) followed by elution using 0.5 N aqueous Ammoniumhydroxide to provide the title compound as a colorless solid (yield: 3.9mg, 83%). [α]_(D)=−40°, c=0.08 (water).

1H NMR (DMSO-d6) δ 7.71 (d, J=9.2 Hz, 1H), 5.38 (m, 1H), 5.29 (m, 1H),3.92 (m, 1H), 3.65 (t, J=8.5 Hz, 1H), 3.43 (m, 1H), 3.33 (m, 1H), 2.98(m, 1H), 2.23 (m, 1H), 1.76 (s, 3H), 1.54 (dd, J=6.7, 1.8 Hz, 3H), 1.46(m, 2H), 1.23 (m, 1H), 0.84 (t, J=7.3 Hz, 3H).

MS: (M+H)=285, (M+Na)+=307, (M−H)−=283.

[α]_(D)=−40°, (c=0.08, water).

EXAMPLE 253

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (MeOD-d₃) δ. 7.8 (d, J=9.3 Hz, 1H), 5.49-5.43 (m, 1H), 5.25 (dd,J=1.95, 9.3 Hz, 1H), 4.38-4.31 (m, 2H), 3.57-3.50 (m, 1H), 3.46 (dd,J=4.9,10.3 Hz, 1H), 3.42 (s, 3H), 3.35-3.32 (m, 2H), 3.27 (s, 3H),3.16-3.09 (m, 1H), 2.46-2.40 (m, 1H), 1.80 (s, 3H), 1.72-1.65 (m, 1H),1.55 (d, J=6.8 Hz, 3H).

MS: (M+H)⁺=315, (M+Na)⁺=337, (M−H)⁻=313, (M+Cl)⁺=349, (2M−H)⁻=627.

EXAMPLE 254

(±)-(2R,3S,5R,1′R,2′R)-2-(1-Acetamido-2,3-dimethoxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (MeOD-d₃) δ. 8.04 (d, J=8.5 Hz, 1H), 5.52-5.48 (m, 1H), 5.27-5.22(m, 1H), 4.32-4.25 (m, 2H), 3.74-3.71 (m, 1H), 3.53 (dd, J=2.4, 10.1 Hz,1H), 3.33-3.25 (m, 2H), 3.31 (s, 3H), 3.25 (s, 3H), 3.21-3.17 (m, 1H),2.42-2.36 (m, 1H), 1.86 (s, 3H), 1.71-1.63 (m, 1H), 1.62 (d, J=7.3 Hz,3H).

MS: (M+H)⁺=315, (M+Na)⁺=337, (M−H)⁻=313, (M+Cl)⁻=349, (2M−H)⁻=627.

EXAMPLE 255

(±)2R,3S,5R,1′R,2R)-2-(1-Acetamido-2-hydroxyethyl-2-hydroxy)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆): δ 7.60 (m, 1H), 5.46 (m, 1H), 5.30 (m, 1H), 4.54 (m,1H), 4.35 (m, 1H), 4.03 (m, 1H), 3.96 (m, 1H), 3.69 (m, 1H), 3.15 (m,1H), 2.40 (m, 1H), 1.98 (m, 2H), 1.80 (s, 3H), 1.70-1.50 (m, 5H), 1.38(m, 3H), 0.83 (m, 3H).

MS: (M+H)+=343, (M−H)⁻=341.

EXAMPLE 256

(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-(3-pentyloxy))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (MeOD-d₃) δ 5.69-5.59 (m, 1H), 5.33-5.25 (m, 1H), 4.39 (m, 1H),4.34 (dd, J=7.8, 10.2 Hz, 1H), 3.73 (dd, J=4.8, 10.2 Hz, 1H), 3.58-3.47(m, 2H), 3.38-3.24 (m, 1H), 3.27-3.20 (m, 1H), 2.61-2.52 (m, 1H), 2.02(s, 3H), 1.90-1.78 (m, 1H), 1.70 (dd, J=1.7, 6.8 Hz, 3H), 1.60-1.50 (m,4H), 0.92 (t, J=7.5 Hz, 6H).

(M+H)⁺=327, (M+Na)⁺=349.

EXAMPLE 257

(±)-(2R,3S,5R,1′S)-2-(1-Acetamido-2-(3-pentyloxy))ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (MeOD-d₃) δ 5.73-5.66 (m, 1H), 5.32-5.25 (m, 1H), 4.36 (dd,J=7.8, 10.2 Hz, 1H), 4.09 (m, 1H), 3.68 (dd, J=6.1, 10.2 Hz, 1H), 3.61(d, J=4.4 Hz, 2H), 3.35-3.23 (m, 1H), 3.24-3.16 (m, 1H), 2.65-2.55 (m,1H), 2.03 (s, 3H), 1.92-1.80 (m, 1H), 1.70 (dd, J=2.0, 7.1 Hz, 3H),1.59-1.47 (m, 4H), 0.94-0.88 (m, 6H).

(M+H)⁺=327, (M+Na)⁺=349.

EXAMPLE 258

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy-3-vinyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 8.01 (d, J=8.6 Hz, 1H), 5.76 (m, 1H), 5.49 (m, 1H),5.25 (m, 1H), 5.05 (m, 2H), 4.28 (m, 1H), 4.02 (m, 1H), 3.77 (m, 1H),3.62 (m, 1H), 3.36 (m, 1H), 3.29 (m, 1H), 3.18 (m, 1H), 2.43 (m, 1H),2.38 (m, 1H), 2.16 (m, 1H), 1.87 (s, 3H), 1.69 (m, 1H), 1.63 (dd, J=6.7,1.2 Hz, 3H), 1.12 (t, J=6.7 Hz, 3H).

MS: (M+H)=325, (M−H)−=323.

EXAMPLE 259

(±)-(2R,3S,5R,1′RS)-2-(1-Acetamido-2-allyloxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 9.16 (m, 2H), 8.13 (d,J=7.5 Hz, 1H), 5.88 (m, 1H),5.50 (m, 1H), 5.15-5.32 (m, 3H), 4.35 (m, 2H), 3.95 (m, 2H), 3.61 (m,1H), 3.40 (m, 2H), 3.20 (m, 1H), 2.40 (m, 1H), 1.87 (s, 3H), 1.72 (m,1H), 1.62 (d, J=6.2, 3H).

MS: (M+1)=297, (M+23)=319, (2M+23)=615.

EXAMPLE 260

(±)-(2R,3S,5R,1′R,2′RS)-2-(1-Acetamido-2-hydroxy-2-(2-ethoxycarbonyl))pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.57 (d, J=10 Hz, 1H), 5.45 (m, 1H), 5.29 (m, 1 -1H),4.35 (m, 1H), 4.09 (m, 1H), 3.68 (m, 1H), 3.44 (m, 1H), 3.17 (m, 1H),2.87 (m, 1H), 2.64 (m, 1H), 2.39 (m, 1H), 1.80 (s, 3H), 1.65-1.56 (m,2H), 1.53 (m, 3H), 1.50-1.30 (m, 3H), 1.21 (t, J=7.5 Hz, 3H), 0.80 (t,J=7.5 Hz, 3H).

MS: (M+H)⁺=385, (M−H)⁻=383.

EXAMPLE 261

(±)-(2R,3S,5R,1′S,3′R)-2-(1-Acetamido-3,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (CD₃OD) δ 5.58-5.70 (m, 1H), 5.24-5.38 (m, 1H), 4.34-4.50 (m,2H), 3.58-3.72 (m, 2H), 3.42-3.48 (d, 2H), 2.50-2.63 (m, 1H), 2.04 (s,3H), 1.77-1.95 (m, 1H), 1.65-1.76 (m, 4H), 1.50-1.63 (m, 1H).

MS: (M+H)⁺=301.

EXAMPLE 262

(±)-(2R,3S,5R,1′S,3′S)-2-(1-Acetamide-3,4-dihydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (CD₃OD) δ 5.58-5.72 (m, 1H), 5.25-5.37 (m, 1H), 4.30-4.45 (m,2H), 3.63-3.77 (m, 2H), 3.44-3.49 (d, 2H), 2.50-2.63 (m, 1H), 2.03 (s,3H), 1.76-1.95 (m, 2H), 1.65-1.75 (m, 4H).

MS: (M+H)⁺=301.

EXAMPLE 263(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-methoxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

263A(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-methoxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound was prepared according to the method described inExample 84A, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester for(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 4.2 mg, 20%).

MS: (M+H)⁺=427, (M+Na)⁺=449, (M−H)⁻=425.

263B(±)-(2R,3S,5R,1′R)-2-(1-Acetamido-2-methoxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

The title compound was prepared according to the method described inExample 41 C, substituting(±)-(2R,3S,5R,1′R)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxyethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 0.0031 g, 100%).

¹H NMR (DMSO-d₆) δ 8.12 (d, J=7.9 Hz, 1H), 5.50 (m, 1H), 5.23 (m, 1H),4.33 (m, 1H), 3.56 (dd, J=9.7, 8.0 Hz, 1H), 3.4-3.3 (m, 2H), 3.26 (s,3H), 3.19 (m, 1H), 2.39 (dt, J=12.8, 7.3 Hz, 1H), 1.86 (s, 3H), 1.71 (m,1H), 1.61 (dd, J=6.7, 1.8 Hz, 3H).

MS: (M+H)⁺=271, (M+Na)⁺=293.

EXAMPLE 264(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

264A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compounds were prepared according to the method described inExample 41B, substituting t-butyl lithium for ethyl magnesium bromide toprovide(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2.5 mg, 11%)

(±)-(2R,3S,5R,1′R,2′S) MS: (M+H)⁺=469; (M−H)⁻=467.

264B(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-hydroxy-4-vinyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The title compound was prepared according to the method described inExample 41C, substituting(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-3-dimethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester in place of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (yield: 2.3 mg, 100%).

¹H NMR (D₂O) δ 5.40 (m, 1H), 5.10 (t, J=5.5 Hz, 1H), 4.13 (t, J=9.2 Hz,1H), 3.46 (m, 1H), 3.22 (d, J=7.3 Hz, 1H), 3.00 (m, 1H), 2.41 (m, 1H),1.70 (s, 3H), 1.45 (m, 1H), 1.39 (d, J=4.9 Hz, 3H), 1.07 (t, J=5.5 Hz,1H), 0.70 (s, 9H).

MS: (M+H)⁺=313.

EXAMPLE 265(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic acid Salt

265A(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl ester.

Sodium bis(trimethylsilyl)amide (7.26 mL, 1.0M in THF, 7.26 mmol) wasadded slowly to a solution of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (3.09 g, 6.6 mmol) in THF (65 mL) at −78° C. Thereaction mixture was stirred at −78° C. for 1 h and then at 0° C. for 20min. Methyl iodide (8.2 mL, 18.8 g, 0.132 mol) was added and the mixturestirred at 0° C. for 20 min and rt for 2 h. The reaction mixture wasthen quenched with saturated aqueous ammonium chloride (20 mL) and water(20 mL) and extracted using ethyl acetate (3×100 mL). The combinedorganic layer was dried over magnesium sulfate, filtered, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 99:1 dichloromethane/methanol followed by 98:2dichloromethane/methanol to give the title compound (2.1 g, 67% yield).This compound exists as a mixture of rotamers at rt. The ¹H NMR spectrumwas therefore acquired at 130° C.

¹H NMR (DMSO-d₆) δ 6.9 (bs, 1H), 5.75 (m, 1H), 5.3 (m, 1H), 4.55 (m,1H), 3.9 (m, 2H), 3.5 (m, 1H), 3.15 (s, 3H), 2.6 (m, 1H), 1.85 (s, 3H),1.6 (d, J=6 Hz, 3H), 1.5-1.25 (m, 4H), 1.40 (bs, 18H), 1.08 (s, 3H),0.85 (t, J=7 Hz, 3H).

MS: (M+H)⁺=483, (M+Na)⁺=505, (M−H)⁻=481.

265B(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt.

(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (4.1 mg, 0.0085 mmol) was reacted withtrifluoroacetic acid (0.8 mL) in dichloromethane (0.2 mL) at roomtemperature for 4 h. The reaction mixture was concentrated in vacuoovernight to provide the title compound (yield: 4.1 mg, 100%) as acolorless oil.

¹H NMR (DMSO-d₆) δ 8.96 (bs, 1H), 8.61 (bs, 1H), 7.61 (d, J=10.3 Hz,1H), 5.45 (m, 1H), 5.28 (m, 1H), 4.33 (t, J=9.8 Hz, 1H), 4.29 (m, 1H),3.59 (m, 1H), 3.2-3.1 (m, 1H), 3.14 (s, 3H), 2.43 (dt, J=12.8, 7.9 Hz,1H), 1.80 (s, 3H), 1.6-1.4 (m, 2H), 1.53 (dd, J=6.7, 1.2 Hz, 3H),1.35-1.25 (m, 3H), 1.19 (s, 3H), 0.80 (t, J=6.7 Hz, 3H).

MS: (M+H)⁺=327, (M+Na)⁺=349, (2M+H)⁺=653, (M−H)⁻=325, (2M−H)⁻=651.

EXAMPLE 266

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

A mixture of 9.88 g (0.083 mol, 6.05 mL) thionyl chloride and 175 mL ofanhydrous ethanol was stirred at rt for 15 min. To this mixture wasadded slowly dropwise a solution of 1.83 g (4.15 mmol)(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt in 25 mL of anhydrous ethanol. Themixture was stirred at room temperature for 18 h and then the solventwas evaporated in vacuo overnight. The residue was purified by columnchromatography on silica gel using 98:2:0.1dichloromethane/methanol/ammonium hydroxide to give the the compound(1.44 g, 98% yield) as a thick colorless oil which solidified uponprolonged standing.

¹H NMR (CDCl₃) 5.48 (d, J=10.8 Hz, 1H), 5.45-5.28 (m, 2H), 4.16 (m, 2H),3.83 (t, J=7.4 Hz, 1H), 3.29 (t, J=7.1 Hz, 1H), 3.17 (s, 3H), 2.97(quintet, J=8.1 Hz, 1H), 2.31 (dt, J=12.9, 7.8 Hz, 1H), 1.95 (s, 3H),1.61 (dd, J=6.5, 1.4 Hz, 3H), 1.55-1.30 (m, 3H), 1.26 (t, J=7.1 Hz, 3H),1.11 (s, 3H), 0.00 (t, J=7.1 Hz, 3H).

MS: (M+H)⁺=355, (M−H)⁻=353.

EXAMPLE 267

(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester

Resolution of the racemic ethyl ester was carried out by chiral HPLCusing a Chiralpak AD column (10 micron particle diameter, ChiralTechnologies, Exton, Pa.) eluting with 98:2 (v/v) hexane/ethanol. Thus,(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ethyl ester (14.8 g, 0.042 mol) provided 6.44 g (44% recovery) of(−)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ethyl ester ([α]=−76.90 in dichloromethane at room temperature) and6.34 g (43% recovery) of(±)-(2S,3R,5S,1′S,2′R)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ethyl ester ([α]=+75.8° in dichloromethane at room temperature).The ¹H NMR and MS data for each of these compounds matched exactly thedata obtained for the racemic mixture.

EXAMPLE 268

(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Ethyl Ester p-Toluenesulfonic Acid Salt

A solution of(−)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ethyl ester (0.269 g, 0.759 mmol) and p-toluenesulfonic acidhydrate (0.144 g, 0.759 mmol) in dichloromethane (15 mL) was stirred atroom temperature for 30 minutes. The solvent was then evaporated invacuo to provide the title compound (yield: 0.390 g, 98%) as a whitepowder.

¹H NMR δ 10.1 (bs, 1H), 9.4 (bs, 1H), 7.78 (d, J=8.1 Hz, 2H), 7.16 (d,J=7.8 Hz, 2H), 6.75 (bd, J=10 Hz, 1H), 5.6-5.4 (m, 2H), 4.49 (t, J=9.5Hz, 1H), 4.28 (m, 1H), 4.22 (q, J=7.2 Hz, 2H), 4.14 (m, 1H), 3.32 (m,1H), 3.24 (s, 3H), 2.48 (m, 2H), 2.35 (s, 3H), 1.94 (s, 3H), 1.93 (dt,J=13.7, 10.5 Hz, 1H), 1.57 (d, J=5.4 Hz, 3H), 1.5-1.4 (m, 3H), 1.37 (s,3H), 1.26 (t, J=7.1 Hz, 3H), 0.85 (t, J=6.8 Hz, 3H).

MS: (M+H)⁺=355, (M−H)⁻=353.

Anal Calcd for C₂₆H₄₂N₂O₇S: C, 59.29; H, 8.04; N, 5.32; S, 6.09. Found:C, 59.24; H, 7.87; N, 5.16; S 6.18.

EXAMPLE 269

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Isopropyl Ester

A mixture of 0.19 g (1.59 mmol, 0. 12 mL) thionyl chloride and 10 mL of2-propanol was stirred at rt for 15 min. To this mixture was addedslowly dropwise a solution of 0.35 g (0.0795 mmol)(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt in 2 mL of 2-propanol. The mixture wasstirred at room temperature for 48 hours and then the solvent wasevaporated in vacuo. The residue was purified by column chromatographyon silica gel using 98:2:0.1 dichloromethane/methanol/ammonium hydroxideto provide the title compound (yield: 9.1 mg, 31%) as a colorless oil.

¹H NMR (CDCl₃) δ 5.5-5.25 (m, 3H), 5.02 (septet, J=6.3 Hz, 1H), 4.15(dd, J=10.2, 7.1 Hz, 1H), 3.79 (t, J=7.5 Hz, 1H), 3.28 (t, J=7.4 Hz,1H), 3.17 (s, 3H), 2.96 (quintet, J=8.3 Hz, 1H), 2.30 (td, J=12.5, 8.2Hz, 1H), 1.94 (s, 3H), 1.62 (dd, J=6.8, 1.6 Hz, 3H), 1.65-1.30 (m, 5H),1.24 (d, J=6.5 Hz, 3H), 1.21 (d, J=6.3 Hz, 3H), 1.11 (s, 3H), 0.90 (t,J=7.1 Hz, 3H).

MS: (M+H)⁺=369, (M−H)⁻=367.

EXAMPLE 270

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Isopropyl Ester p-Toluenesulfonic Acid Salt

A mixture of(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid isopropyl ester (8.4 mg, 0.0228 mmol) and p-toluenesulfonic acidmonohydrate (0.0043 g, 0.0228 mmol) in 1 mL of dichloromethane wasstirred at rt for 1 h. The solvent was evaporated in vacuo to providethe desired product (yield: 12.0 mg, 97%) as a white powder.

¹H NMR (CDCl₃) δ 9.9 (bs, 1H), 9.45 (bs, 1H), 7.79 (d, J=8.1 Hz, 2H),7.15 (d, J=7.8 Hz, 2H), 6.57 (bd, J=8.9 Hz, 1H), 5.53 (m, 2H), 5.07(quintet, J=6.3 Hz, 1H), 4.50 (t, J=9.5 Hz, 1H), 4.25 (bs, 1H), 4.10(bs, 1H), 3.34 (m, 1H), 3.24 (s, 3H), 2.50 (m, 1H), 2.35 (s, 3H), 1.95(s, 3H), 1.9 (m, 1H), 1.6-1.2 (m, 6H), 1.35 (s, 3H), 1.25 (d, J=6.4 Hz,3H), 1.23 (d, 3H), 0.85 (t, J=7.0 Hz, 3H).

MS: (M+H)⁺=369, (M−H)⁻=367.

EXAMPLE 271

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester

A mixture of(±)-(2R,3S,5R,1′R,2′S)-1-t-butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (0.4123 g, 0-855 mmol) and trifluoroacetic acid (2.93g, 25.7 mmol) in 10 mL dichloromethane was stirred at rt for 1.5 h. Thesolvent was evaporated in vacuo and the residue purified bychromatography on silica gel, eluting with 98:2:0.1dichloromethane/methanol/ammonium hydroxide to provide the desiredproduct (yield: 0.168 g, 51%) as a colorless oil.

¹H NMR (CDCl₃) δ 5.5-5.25 (m, 3H), 4.15 (dd, J=10.1, 7.2 Hz, 1H), 3.73(t, J=7.4 Hz, 1H), 3.26 (t, J=7.1 Hz, 1H), 3.17 (s, 3H), 2.94 (quintet,J=8.3 Hz, 1H), 2.28 (td, J=12.5, 7.8 Hz, 1H), 1.93 (s, 3H), 1.61 (dd,J=6.4, 1.4 Hz, 3H), 1.58-1.20 (m, 5H), 1.44 (s, 9H), 1.11 (s, 3H), 0.90(t, J=7.1 Hz, 3H).

MS: (M+H)⁺=383, (M−H)⁻=381.

EXAMPLE 272 (±)-(2R,3S35R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl ester p-Toluenesulfonic Acid Salt

A mixture of(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid t-butyl ester (0.161 g, 0.421 mmol) and p-toluenesulfonic acidmonohydrate (0.080 g, 0.421 mmol) in 10 mL of dichloromethane wasstirred at rt for 1 h. The solvent was evaporated in vacuo to providethe desired product (yield: 0.230 g, 99%) as a white powder.

¹H NMR (CDCl₃) δ 9.2 (bs, 1H), 9.35 (bs, 1H), 7.79 (d, J=6.4 Hz, 2H),7.15 (d, J=8.4 Hz, 2H), 6.8 (bd, J=9.9 Hz, 1H), 5.6-5.4 (m, 2H), 4.50(t, J=9.5 Hz, 1H), 4.22 (bs, 1H), 4.10 (bs, 1H), 3.4-3.3 (m, 1H), 3.24(s, 3H), 2.46 (m, 1H), 2.34 (s, 3H), 1.94 (s, 3H), 1.86 (m, 1H), 1.64(s, 3H), 1.57 (d, J=5.1 Hz, 3H), 1.52-1.40 (m, 2H), 1.46 (s, 9H), 1.38(s, 3H), 1.3-1.2 (m, 1H), 0.84 (t, J=6.8 Hz, 3H).

MS: (M+H)⁺=383, (M−H)⁻=381.

Anal. Calcd for C₂₈H46N₂O₇S: C, 60.62; H, 8.36; N, 5.05; S, 5.78. Found:C, 60.64; H, 8.14; N, 4.96; S, 5.70.

EXAMPLE 273

(−)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid

A solution of(−)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ethyl ester (0.528 g, 1.49 mmol) and lithium hydroxide (72 mg, 3.0mmol) in methanol (75 mL) and water (25 mL) was stirred at rt for 6 h.Following the addition of 100 mL of 0.1 N HCl the mixture was evaporatedin vacuo to provide a white solid. This material was dissolved in water(25 mL) and adsorbed on 15 g of DOWEX 50WX8-400 strongly acidicion-exchange resin (resin had been prepared by washing with waterfollowed by 0.5 N ammonium hydroxide followed by 1.0 N hydrochloric acidfollowed by water). After washing the resin with water (250 mL), thedesired product was eluted using 0.5 N ammonium hydroxide (250 mL) toprovide the desired product (yield: 0.460 g, 90%) as a white solid.[α]=−54.6° in water at rt.

¹H NMR (D₂O) δ 5.61 (dq, J=8.9, 7.2 Hz, 1H), 5.31 (m, 1H), 4.35 (d,J=10.2 Hz, 1H), 4.10 (t, J=8.9 Hz, 1H), 3.59 (t, J=10.0 Hz, 1H), 3.26(s, 3H), 3.14 (quintet, J=8.5 Hz, 1H), 2.54 (dt, J=13.6, 7.8 Hz, 1H),2.16 (m, 1H), 1.95 (s, 3H), 1.75-1.6 (m, 1H), 1.57 (dd, J=6.8, 1.3 Hz,3H), 1.40 (m, 1H), 1.35-1.25 (m, 2H), 1.24 (s, 3H), 0.85 (t, J=7.0 Hz,3H), 0.78 (m, 1H).

MS (M+H)⁺=327, (M+Na)⁺=349, (M−H)⁻=325, (2M−H)⁻=651.

EXAMPLE 274

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Isopropyl Ester

¹H NMR (CDCl₃, 500 MHz) δ 5.50-5.45 (m, 1H), 5.35 (d, 1H, J=7 Hz),5.30-5.25 (m, 1H), 5.10-5.0 (m, 1H), 3.80-3.75 (m, 2H), 3.62-3.57 (m,1H), 3.17-3.12 (m, 1H), 3.10-3.02 (m, 1H), 2.42-2.37 (m, 1H), 1.93 (s,3H), 1.61 (d, 3H, J=5 Hz), 1.52-1.42 (m, 3H), 1.28-1.20 (m, 8H), 0.98(t, 3H, J=7 Hz).

EXAMPLE 275

(±)-(2R,3S5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Isobutyl Ester

¹H NMR (DMSO-d₆, 500 MHz) δ 7.49 (d, 1H, J=10 Hz), 5.32-5.24 (m, 2H),3.92-3.80 (m, 2H), 3.75 (t, 1H, J=7.7 Hz), 3.48-3.32 (m, 6H), 3.10-3.04(m, 1H), 2.90-2.83 (m, 1H), 2.45 (s, 1H), 2.29-2.2.22 (m, 1H), 2.19 (s,1H), 1.75 (s, 2H), 1.52 (d, 2H, J=5 Hz), 1.06 (s, 3H), 0.90 (d, 6H, J=5Hz).

EXAMPLE 276

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid tert-Butyl Ester

¹H NMR (DMSO-d₆, 500 MHz) δ 8.95 (s, br, 1H), 7.88 (d, 1H, J=9.5 Hz),5.50-5.43 (m, 1H), 5.35-5.24 (m, 2H), 4.30-4.25 (m, 1H), 4.03-3.95 (m,1H), 3.75-3.68 (m, 1H), 2.42-2.33 (m, 1H), 1.82 (s, 3H), 1.60 (d, 3H,J=6 Hz), 1.58 (d, 3H, J=6 Hz), 1.45 (s, 9H), 1.30-1.22 (m, 2H), 0.85 (t,3H, J=7.5 Hz).

EXAMPLE 277

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Benzyl Ester

¹H NMR (DMSO-d₆, 500 MHz) δ 7.49 (d, 1H, J=9.5 Hz), 7.40-7.30 (m, 5H),5.32-5.24 (m, 2H), 5.19-5.10 (m, 3H), 3.70 (t, 1H, J=7 Hz), 3.62-3.55(m, 2H), 3.44-3.40 (m, 1H), 3.10-3.05 (t, 1H, J=7 Hz), 2.90-2.82 (m,1H), 2.30-2.21 (m, 1H), 1.75 (s, 3H), 1.53 (d, 3H, J=6 Hz), 1.45-1.39(m, 2H), 0.80 (t, 3H, J=7.5 Hz).

EXAMPLE 278

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Butyl Ester

¹H NMR (DMSO₆, 500 MHz) δ 9.2 (s, br, 1H), 7.89 (d, 1H, J=9.5 Hz), 7.48(d, 2H, J=8 Hz), 7.10 (d, 2H, J=8 Hz), 5.50-5.42 (m, 1H), 5.35-5.25 (m,1H), 4.42-4.37 (m, 1H), 4.21-4.13 (m, 2H), 4.07-4.00 (m, 1H), 3.76-3.69(m, 1H), 3.47-3.40 (m, 1H), 3.20-3.10 (m, 1H), 2.47-2.40 (m, 1H), 2.27(s, 3H), 1.81 (s, 3H), 1.68-1.57 (m, 4H), 1.38-1.22 (m, 5H), 0.92-0.81(m, 5H).

EXAMPLE 279

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Pentyl Ester

¹H NMR (DMSO-d₆, 500 MHz) δ 7.50 (d, 1H, J=9.5 Hz), 5.35-5.23 (m, 2H),4.12-4.00 (m, 2H), 3.30 (s, 3H), 3.72 (t, 1H, J=5.0 Hz), 3.60-3.53 (m,1H), 3.43-3.40 (m, 1H), 3.10-3.05 (m, 1H), 3.90-3.83 (m, 1H), 2.27-2.20(m, 1H), 1.50-1.35 (m, 3H), 1.75 (s, 3H), 1.60-1.50 (m, 4H), 1.32-1.15(m, 5H), 0.9-0.8 (m, 5H).

EXAMPLE 280

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-hydroxy)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid (2-Methyl)benzyl Ester p-Toluenesulfonic Acid Salt

¹H NMR (DMSO-d₆, 500 MHz) δ 9.05 (d, br 1H), 7.90 (d, 1H, J=9.5 Hz),7.47 (d, 2H, J=8.0 Hz), 7.39-7.20 (m, 4H), 7.10 (d, 2H, J=8.0 Hz),5.50-5.42 (m, 1H), 5.29-5.20 (m, 2H), 4.05-4.00 (m, 1H), 3.75-3.70 (m,1H), 2.45-2.40 (m, 1H), 2.22 (s, 2H), 2.29 (s, 3H), 1.81 (s, 3H),1.67-1.50 (m, 5H), 1.30-1.22 (m, 4H), 0.88-0.82 (t, 3H, J=7.5 Hz).

EXAMPLE 281

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Amyl Ester

A mixture of 0.054 g (0.45 mmol, 0.033 mL) thionyl chloride and 0.64 g2,2-dimethyl-1-propanol in 1 mL anhydrous toluene was stirred at rt for15 min. To this mixture was added in one portion 0.011 g (0.0227 mmol)(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt. The mixture was stirred at rt for 18 hand then the solvent was evaporated in vacuo. The residue was purifiedby column chromatography on silica gel using 98:2:0.1dichloromethane/methanol/ammonium hydroxide to give the title compound(6.5 mg, 66% yield) as a colorless oil.

¹H NMR (CDCl₃) δ 5.5-5.25 (m, 3H), 4.17 (dd, J=10.2, 7.1 Hz, 1H), 3.89(t, J=7.8 Hz, 1H), 3.86 (d, J=10.5 Hz, 1H), 3.75 (d, J=10.5 Hz, 1H),3.31 (t, J=7.7 Hz, 1H), 3.17 (s, 3H), 2.98 (quintet, J=8.3 Hz, 1H), 2.33(dt, J=12.9, 7.8 Hz, 1H), 1.94 (s, 3H), 1.61 (dd, J=6.6, 1.3 Hz, 3H),1.65-1.30 (m, 5H), 1.12 (s, 3H), 0.93 (s, 9H), 0.90 (t, J=7.1 Hz, 3H).

MS: (M+H)⁺=397, (M+Na)⁺=419, (M−H)⁻=395.

EXAMPLE 282

(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid Isobutyl Ester

A mixture of 0.0714 g (0.60 mmol, 0.044 mL) thionyl chloride and 2 mL2-methyl-1-propanol was stirred at rt for 15 min. To this mixture wasadded amethoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid trifluoroacetic acid salt in 1 mL of 2-methyl-1-propanol. Themixture was stirred at rt for 48 h and then the solvent was evaporatedin vacuo. The residue was purified by column chromatography on silicagel using 98:2:0.1 dichloromethane/methanol/ammonium hydroxide to givethe title compound (6.5 mg, 57% yield) as a colorless oil.

¹H NMR (CDCl₃) δ 5.5-5.25 (m, 3H), 4.16 (dd, J=10.4, 7.3 Hz, 1H),3.95-3.8 (m, 3H), 3.30 (t, J=7 3 Hz, 1H), 3.17 (s, 3H), 2.97 (quintet,J=8.3 Hz, 1H), 2.32 (dt, J=12.9, 7.8 Hz, 1H), 1.95 (s, 3H), 1.93 (m,1H), 1.61 (dd, J=6.6, 1.5 Hz, 3H), 1.6-1.2 (m, 5H), 1.11 (s, 3H), 0.92(d, J=6.4 Hz, 6H), 0.90 (t, J=7.0 Hz, 3H).

EXAMPLE 283(±)2R,3S,5R,1′R,2′R)-2-(1-acetamido-2-hydroxy-2-ethenyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.58 (d, J=10.4 Hz, 1H), 6.02 (dd, J=17.1, 10.4 Hz,1H), 5.5-5.4 (m, 2H), 5.30 (dd, J=11.0, 1.8 Hz, 1H), 5.20 (m, 1H),4.35-4.30 (m, 2H), 3.38 (t, J=9.2 Hz, 1H), 3.07 (quintet, J=8.8 Hz, 1H),2.42 (dt, J=13.4, 7.9 Hz, 1H), 1.80 (s, 3H), 1.55 (m, 1H), 1.51 (dd,J=6.7, 1.8 Hz, 3H), 1.43-1.30 (m, 4H), 1.22 (m, 1H), 0.81 (t, J=7.0 Hz,3H).

MS: (M+H)⁺=325, (M+Na)⁺=347, (2M+H)⁺=649, (M−H)⁻=323, (2M−H)⁻=647.

EXAMPLE 284(±)-(2R,3S,5R,1′R,2′R)-2-(1-acetamido-2-methoxy-2-ethenyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 7.58 (d, J=10.4 Hz, 1H), 6.02 (dd, J=17.1, 10.4 Hz,1H), 5.5-5.4 (m, 2H), 5.30 (dd, J=11.0, 1.8 Hz, 1H), 5.20 (m, 1H),4.35-4.30 (m, 2H), 3.38 (t, J=9.2 Hz, 1H), 3.07 (quintet, J=8.8 Hz, 1H),2.42 (dt, J=13.4, 7.9 Hz, 1H), 1.80 (s, 3H), 1.55 (m, 1H), 1.51 (dd,J=6.7, 1.8 Hz, 3H), 1.43-1.30 (m, 4H), 1.22 (m, 1H), 0.81 (t, J=7.0 Hz,3H).

EXAMPLE 285

285A(±)-(2R,3RS,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-ethoxyethyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester

(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl2-(1-acetamido-2-triisopropylsilyloxy)ethyl-3-hydroxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester (1.06 g, 1.90 mmol) in 40 ml of dichloromethane wasreacted with pyridinium p-toluenesulfonate (95 mg, 0.38 mmol) and ethylvinyl ether (0.36 ml, 3.80 mmol) 1 hour at room temperature. Thereaction was quenched with saturated aqueous NaHCO₃, extracted withdichloromethane (5×30 ml). The combined organic layers were dried overNa₂SO₄ and concentrated to give the crude title compound (yield: 1.2 g,100%).

MS: (M+H)⁺=631.

285B(±)-(42R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)ethyl-3-ethoxyethyloxymethyl-pyrrolidine-5-carboxylicacid t-butyl ester

The product of Example 285A (1.2 g, 1.90 mmol) in THF (60 ml) wasreacted with tetrabutyl ammonium fluoride (1M in THF) (1.90 ml, 1.90mmol) for 60 minutes at room temperature. Water was added followed byextraction using dichloromethane (5×40 ml). This organic layers weredried over Na₂SO₄, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel using 10% methanol indichloromethane to provide the title compound as a colorless oil (yield:791.6 mg, 87.7%).

¹H NMR (CDCl₃): δ 1.18 (td, 3H), 1.26 (dd, 3H), 1.44 (s, 9H), 1.47 (s,9H), 1.85 (m, 1H), 2.00 (s, 3H), 2.39 (m, 1H), 2.55 (m, 1H), 3.27-3.67(m, 6H), 3.83 (m, 1H), 3.92 (d, 1H), 4.12 (dt, 1H), 4.26 (m, 1H), 4.64(m, 1H), 6.36 (br d, 1H).

MS: (M+H)⁺=475.

285C(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-1-formyl)methyl-3-ethoxyethyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The product of Example 285B (790.0 mg, 1.66 mmol) was reacted withDess-Martin Periodinane (850 mg, 2.0 mmol) in dichloromethane (40 ml) atroom temperature for 2 hours. The reaction was quenched with 1M aqueoussodium thiosulfate (40 ml) and extracted with dichloromethane (5×40 ml).The organic layers were dried over sodium sulfate, filtered, andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using ethyl acetate to provide the title compound as awhite foamy solid (yield: 707.1 mg, 89.9%).

¹H NMR (CDCl₃): δ 1.18 (td, 3H), 1.27 (dd, 3H), 1.42 (s, 9H), 1.47 (s,9H), 1.71 (m, 1H), 2.08 (s, 3H), 3.34-3.67 (m, 4H), 3.92 (dd, 1H), 4.18(dd, 1H), 4.65 (m, 1H), 4.89 (ddd, 1H), 7.15 (m, 1H), 9.46 (s, 1H).

MS: (M+H)⁺=473.

285D (±)-(2R,3R,5R,1′R,2′R and2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy)butyl-3-ethoxyethyloxymethylpyrrolidine-5-carboxylicAcid t-Butyl Ester

The product of Example 285C (700 mg, 1.48 mmol) in THF (15 ml) was addeddropwise to a solution of ethylmagnesium chloride (3.0M in ether) (3.0ml, 8.9 mmol) in THF (15 ml) at room temperature and reacted for 30minutes. The reaction was quenched with saturated aqueous ammoniumchloride (15 ml) followed by extraction with dichloromethane (5×20 ml).The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo, to provide the crude title compound (yield: 756.2mg, 100%).

MS: (M+H)⁺=503.

285E(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-oxo)butyl-3-ethoxyethyloxymethylpyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 285C, substituting the product of Example 285D in place of theproduct of Example 285B (yield: 574.2 mg, 77.4%).

¹H NMR (CDCl₃): δ 1.04 (t, J=7.2 Hz, 3H), 1.18 (td, J=6.9 3.6 Hz, 3H),1.24 (dd, J=5.4, 1.2 Hz, 3H), 1.45 (s, 9H), 1.46 (s, 9H), 1.65 (m, 1H),2.04 (s, 3H), 2.28 (m, 1H), 2.42 (m, 1H), 2.63 (qd, J=7.2, 1.5 Hz, 2H),3.25 (dd, J=9.3, 6.3 Hz, 1H), 3.36-3.46 (m, 2H), 3.54-3.61 (m, 2H),4.09-4.18 (m, 2H), 4.61 (t, J=5.1 Hz, 1H), 5.23 (br t, J=7.2 Hz, 1H).

MS: (M+H)⁺=501.

285F(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-hydroxy-2-vinyl)butyl-3-ethoxyethyloxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 285D, substituting compound the product of Example 285E in placeof the product of Example 285C and substituting vinyl magnesium bromidein place of ethyl magnesium bromide (yield: 272.1 mg, 45.2%).

MS: (M+H)⁺=529.

285G(±)-(2R,3R,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-vinyl)butyl-3-ethoxyethyloxymethylpyrrolidine-5-carboxylicAcid t-Butyl Ester

The product of Example 285F (200 mg, 0.38 mmol) in THF (6 ml) wasreacted with sodium bis(trimethylsilyl)amide (1.0M in THF, 0.76 ml, 0.76mmol) at −78° C. for 45 minutes then at 0° C. for 15 minutes. Methyliodide (2.4 ml, 38.0 mmol) was added to the reaction at 0° C. Stirringwas continued at 0° C. for 30 minutes then at room temperature for 2hours. The reaction was quenched with saturated aqueous ammoniumchloride (10 ml) followed by extraction using dichloromethane (5×20 ml).The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 5% methanol in dichloromethane to provide the titlecompound (yield:

202.0 mg, 98.4%).

MS: (M+H)⁺=543.

285H(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-ethyl)butyl-3-ethoxyethyloxymethylpyrrolidine-5-carboxylicAcid t-Butyl Ester

The product of Example 285F (200 mg, 0.369 mmol) and 10% Pd—C (100 mg)were stirred under 1 atmosphere of hydrogen in ethyl acetate (50 ml) for2 hours. The reaction was filtered and concentrated, to give the crudetitle compound (yield: 198.1 mg, 98.7%).

MS: (M+H)⁺=545.

285I(±)-(2R,3R,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-ethyl)butyl-3-hydroxymethyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The product of Example 285H (196.0 mg, 0.36 mmol) was dissolved in THF(20 ml) and treated with 0.2N hydrochloric acid (20 ml) at roomtemperature for 2 hour. The reaction was quenched with saturated aqueoussodium bicarbonate followed by extraction using dichloromethane (5×20ml). The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 5% methanol in dichloromethane to provide the titlecompound (yield: 103.2 mg, 60.7%).

¹H NMR (CDCl₃) (mixture of two rotamers) δ: 0.87, 0.89 (two t, J=7.5 Hz,3H), 1.06, 1.26 (two t, J=7.5 Hz, 3H), 1.45, 1.46 (two s, 9H), 1.52,1.55 (two s, 9H), 1.73-1.94 (m, 5H), 1.98, 1.99 (two s, 3H), 2.29-2.42(m, 1H), 2.66-2.91 (m, 1H), 3.27, 3.28 (two s, 3H), 3.51-3.72 (m, 2H),4.00-4.11 (m, 1H), 4.18-4.29 (m, 1H), 4.67, 4.70 (two dd, 1H), 5.76,5.81 (two br d, 1H).

MS: (M+H)⁺=473.

285J (±)-(2R,3R,5R,1′R)-14-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-ethyl)butyl-3-formylpyrrolidine-5-carboxylicAcid t-Butyl Ester

The title compound was prepared according to the method described inExample 285C, substituting the product of Example 285I in place of theproduct of Example 285B (yield: 40.1 mg, 80.5%).

MS: (M+H)⁺=471.

285K(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

A suspension of ethyl triphenylphosphonium bromide (180 mg, 0.48 mmol)in anhydrous toluene (2 ml) was reacted with potassium t-butoxide (1.0 Min THF, 0.32 mmol) at room temperature for 14 hours. The product ofExample 285J (38 mg, 0.081 mmol) in toluene (2 ml) was added dropwise tothe above mixture and stirred for 1 hour. The reaction was quenched withsaturated aqueous ammonium chloride and extracted with dichloromethane(5×10 ml). The organic layer was washed with brine, dried over Na₂SO₄,filtered and concentrated in vacuo. The residue was purified bychromatography on silica gel using 50% ethyl acetate/hexanes to providethe title compound (yield: 20.1 mg, 53.8%).

¹H NMR (CDCl₃) (mixture of rotamers) δ: 0.84 0.91 (3H), 0.97-1.11 (3H),1.42-1.47 (9H), 1.54-1.55 (9H), 1.60-1.64 (3H), 1.66 (1H), 1.72-1.80(4H), 1.97-1.99 (3H), 2.42-2.58 (1H), 3.23-3.25 (3H), 3.50-3.73 (1H),4.03-4.18 (2H), 4.67-4.73 (1H), 5.29-5.38 (1H), 5.57-5.71 (1H),5.83-6.02 (1H).

MS: (M+H)⁺=483.

285L(±)-(2R,3S,5R,1′R)-2-(1-acetamido-2-methoxy-2-ethyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The product of Example 285K (17.0 mg, 0.035 mmol) was reacted withtrifluoroacetic acid (0.8 mL) in dichloromethane (0.2 mL) at roomtemperature for 4 hours. The reaction was concentrated in vacuo andtriturated with dichloromethane (4×0.2 ml) to provide the title compound(yield: 15.6 mg, 100%) as an off white solid.

¹H NMR (DMSO-d₆) δ 0.81 (t, 3H), 0.96 (t, 3H), 1.29 (m, 1H), 1.53 (dd,3H), 1.55-1.65 (m, 3H), 1.70 (m, 1H), 1.82 (s, 3H), 2.45 (m, 1H), 3.10(m, 1H), 3.17 (s, 3H), 3.72 (m, 1H), 4.24 (m, 1H), 4.39 (t, 1H), 5.29(m, 1H), 5.45 (m, 1H), 7.58 (d, 1H), 8.50 (br s, 1H), 9.03 (br s, 1H).

EXAMPLE 286(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methyl-2,3-dimethoxy)ethyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

286A1(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-3-ethoxyethyloxy-2-hydroxy)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester and 286A2(±)-(2R,3S,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-3-ethoxyethyloxy-2-hydroxypropyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

(Ethoxyethyloxymethyl)tributylstannane (prepared according to theprocedure of W. Clark Still, J. Am. Chem. Soc., 100, 1481 (1978)) (575mg, 1.46 mmol) in THF (4 ml) was reacted with n-butyllithium (1.6M, 0.6ml, 0.96 mmol) at −78° C. for 15 minutes followed by the product ofExample 41A (70 mg, 0.17 mmol) in THF (2 ml). The mixture was stirred at−78° C. for an additional 30 minutes, quenched with saturated aqueousammonium chloride (3 ml) followed by extraction using dichloromethane(5×10 ml). The organic layer was dried over magnesium sulfate, filteredand concentrated iii vacuo. The residue was separated by columnchromatography on silica gel using 5% methanol in dichloromethane toprovide the title compounds 286A1 (yield: 25.1 mg, 28.7%) and 286A2(yield: 30.9 mg, 35.3%) as white foamy solids.

286A1: ¹H NMR (CDCl₃): δ 1.20 (dt, J=7.2, 2.4 Hz, 3H), 1.30 (dd, J=5.4,3.9 Hz, 3H), 1.44 (s, 9H), 1.47 (s, 9H), 1.61 (m, 1H), 1.65 (dd, J=6.6,1.5 Hz, 3H), 2.04 (s, 3H), 2.62 (m, 1H), 3.38-3.70 (m, 8H), 4.23 (dd,J=9.3, 5.1 Hz, 1H), 4.67 (qd, J=5.1, 2.4 Hz, 1H), 4.37-4.48 (m, 2H),7.77 (br t, J=9.9 Hz, 1H).

286A2: ¹H NMR (CDCl₃): δ 1.19 (dt, J=7.2, 2.4 Hz, 3H), 1.29 (t, J=5.1Hz, 3H), 1.44 (s, 9H), 1.46 (s, 9H), 1.54 (dd, 3H), 1.64 (m, 1H), 2.00(s, 3H), 2.66 (m, 1H), 3.13 (m, 1H), 3.41-3.49 (m, 2H), 3.59-3.69 (m,2H), 3.75 (d, J=9.9 Hz, 1H), 3.89 (td, J=10.2, 3.0 Hz, 1H), 4.15 (ddd,J=10.2, 3.0, 1.2 Hz, 1H), 4.65 (dd, J=9.6, 5.1 Hz, 1H), 4.72 (dd, J=6.6,4.8 Hz, 1H), 5.35 (m, 1H), 5.60 (br t, J=10.2 Hz, 1H), 5.99 (br d,J=10.2 Hz, 1H).

286B(±)-(2R,3S,5R,1′R)-1-t-Butoxycarbonyl-2-(1-acetamido-3-ethoxyethyloxy-2-oxo)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The products of Example 286A (298.0 mg, 0.58 mmol) were reacted withDess-Martin Periodinane (368.4 mg, 0.87 mmol) in dichloromethane (20 ml)at room temperature for 2 hours. The reaction was quenched with 1Maqueous sodium thiosulfate (20 ml) and extracted with dichloromethane(5×20 ml). The organic layer was dried over sodium sulfate, filtered,and concentrated in vacuo. The residue was purified by columnchromatography on silica gel using ethyl acetate to provide the titlecompound as a white foamy solid (yield. 254.2 mg, 85.6%).

¹H NMR (CDCl₃): δ 1.17 (t, 3H), 1.31 (dd, 3H), 1.41 (s, 9H), 1.46 (s,9H), 1.56 (m, 1H), 1.64 (dt, 3H), 2.06 (s, 3H), 2.45 (m, 1H), 3.47 (m,2H), 3.62 (m, 2H), 4.12-4.48 (m, 3H), 4.75 (m, 1H), 4.96 (ddd, 1H), 5.29(m, 1H), 5.58 (m, 1H), 7.83 (br q, 1H).

MS: (M+H)⁺=513.

286C(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-3-ethoxyethyloxy-2-hydroxy-2-methyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The product of Example 286B (60.0 mg, 0.117 mmol) in THF (2 ml) wasadded dropwise to a solution of methylmagnesium bromide (3.0M in ether)(0.2 mL, 0.59 mmol) in THF (2 ml) at room temperature and reacted for 60minutes. The reaction was quenched with saturated aqueous ammoniumchloride (2 ml) followed by extraction using dichloromethane (5×10 ml).The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo, to provide the title compound (yield: 56.0 mg,90.5%).

MS: (M+H)⁺=529.

286D(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2,3-dihydroxy-2-methyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The product of Example 286C (55.0 mg, 0.104 mmol) was dissolved in THF(5 ml) and reacted with 0.1N hydrochloric acid (5 ml) at roomtemperature for 0.5 hour. The reaction was quenched with saturatedaqueous sodium bicarbonate followed by extraction using dichloromethane(5×10 ml). The organic layer was dried over sodium sulfate, filtered andconcentrated in vacuo. The residue was purified by column chromatographyon silica gel using 5% to 10% methanol in dichloromethane to provide thetitle compound (yield: 29.1 mg, 61.3%).

1H NMR (CDCl₃) δ: 1.17 (s, 3H), 1.43 (s, 9H), 1.46 (s, 9H), 1.63 (dd,3H), 1.65 (m, 1H), 2.06 (s, 3H), 2.64 (s, 1H), 2.83 (m, 1H), 3.16 (m,1H), 3.33 (m, 1H), 3.44 (m, 1H), 4.01 (br s, 1H), 4.23 (m, 2H), 4.48 (m,1H), 5.37-5.55 (m, 2H), 8.05 (br d, 1H).

286E(±)-(2R,3S,5R,1′R,2′R)-1-t-Butoxycarbonyl-2-(1-acetamido-2,3-dimethoxy-2-methyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid t-Butyl Ester

The product of Example 286D (28.0 mg, 0.061 mmol) in THF (2 ml) wasreacted with sodium bis(trimethylsilyl)amide (1.0M in THF, 184 μl, 0.184mmol) at −78° C. for 45 minutes and then 0° C. for 15 minutes. Methyliodide (190 μl, 3.05 mmol) was added to the mixture at 0° C. and stirredat 0° C. for 30 minutes then at room temperature for 1 h. The reactionwas quenched with saturated aqueous ammonium chloride (2 ml) followed byextraction using dichloromethane (5×10 ml). The organic layer was driedover sodium sulfate, filtered and concentrated in vacuo. The residue waspurified by column chromatography on silica gel using 5% methanol indichloromethane to provide the title compound (yield: 28.2 mg, 94.5%).

¹H NMR (CDCl₃) (the major rotamer) δ: 1.28 (s, 3H), 1.44 (s, 9H), 1.46(s, 9H), 1.63 (dd, J=7.2, 1.8 Hz, 3H), 1.70 (m, 1H), 2.01 (s, 3H), 2.49(m, 1H), 3.24 (s, 3H), 3.25 (d, 1H), 3.35 (s, 3H), 3.38 (m, 2H), 3.87(br s, 1H), 4.11 (dd, J=10.5, 1.5 Hz, 1H), 4.80 (m, 1H), 5.37 (m, 1H),5.63 (td, J=10.2, 2.1 Hz, 1H), 6.46 (br d, J=8.7 Hz, 1H).

286F(±)-(2R,3S,5R,1′R,2′R)-2-(1-acetamido-2,3-dimethoxy-2-methyl)propyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

The product of Example 286E (10.2 mg, 0.021 mmol) was reacted withtrifluoroacetic acid (0.8 ml) in dichloromethane (0.2 ml) at roomtemperature for 4 hours. The reaction was concentrated in vacuo andtriturated with dichloromethane (4×0.2 ml) to provide the title compound(yield: 9.2 mg, 98.9%) as an off white solid.

¹H NMR (DMSO-d₆) δ: 1.13 (s, 3H), 1.56 (dd, 3H), 1.63 (m, 1H), 1.84 (s,3H), 2.45 (dt, 1H), 3.18 (m, 1H), 3.19 (d_(AB), J=11.0 Hz, 1H), 3.22 (s,3H), 3.24 (s, 3H), 3.41 (d_(AB), J=11.0 Hz, 1H), 3.69 (t, 1H), 4.28 (t,1H), 4.46 (t, 1H), 5.30 (tq, 1H), 5.46 (dq, 1H), 7.46 (d, J=10.0 Hz,1H), 8.75 (br s, 2H).

MS: (M+H)⁺=329.

EXAMPLE 287(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)butyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Trifluoroacetic Acid Salt

¹H NMR (DMSO-d₆) δ 0.75 (t, J=4.5 Hz, 3H), 1.19 (s, 3H), 1.33 (td,J=9.0, 4.5 Hz, 1H), 1.53 (dd, J=4.2, 0.9 Hz, 3H), 1.56 (q, J=5.7 Hz,2H), 1.79 (s, 3H), 2.43 (dt, J=8.1, 4.5 Hz, 1H), 3.14 (s, 3H), 3.15 (m,1H), 3.59 (br m, 1H), 4.30 (br m, 1H), 4.34 (t, J=6.0, 0.9 Hz, 1H), 5.28(td, J=6.0, 0.9 Hz, 1H), 5.46 (dq, J=6.6, 4.2 Hz, 1H), 7.59 (d, J=6.0Hz, 1H), 8.61 (br s, 1H), 8.97 (br s, 1H).

MS: (M+H)⁺=313.

EXAMPLE 288(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

288A tert-Butyl(2R,3S)-2-((S)-((tert-butyl(dimethyl)silyl)oxy)((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate

The title compound was prepared according to the procedure described inTetrahedron Asymmetry, 1996, 1167-1180.

288B tert-Butyl(2R,3S)-2-((S)-((tert-butyl(dimethyl)silyl)oxy)((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)-pyrrolidine-5-carboxylate

To a solution of copper bromide/dimethyl sulfide (5.9 g, 28.8 mmol) inTHF (100 mL) at −78° C. was added 1-propenylmagnesium bromide (0.5M inTHF, 113 mL, 56.5 mmol) over 1.5 h followed by trimethylsilyl chloride(2.26 mL, 17.8 mmol) in THF (28 mL). To this solution was added theproduct of example 288A (2.44 g, 5.71 mmol) in THF (20 mL) at −78° C.,and the reaction mixture was warmed to −22° C. for 2 h. The reactionmixture was quenched with sat. NH₄Cl and warmed to 25° C. The mixturewas extracted with ethyl acetate, the organic layer was separated,dried, filtered, and the solvent was evaporated. The crude residue waspurified by column chromatography on silica gel using 80% hexane/ethylacetate to give title compound (2.5 g, 93%).

¹H NMR (CDCl₃) δ 5.52-5.40 (m, 2H), 4.15-4.00 (m, 3H), 3.92 (d, 1H),3.74 (dd, 1H), 3.33 (t, 1H), 2.92 (dd, 1H), 2.13 (dd, 1H), 2.65 (d, 3H),1.53 (s, 9H), 1.30 (d, 6H), 0.88 (s, 9H), 0.12 (d, 6H).

MS: (M+H)⁺=470, (M+Na)⁺=492.

288C tert-Butyl(2R,3S,5R)-2-((S)-((tert-butyl(dimethyl)silyl)oxy)((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-cyano-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

i. To a solution of the product of example 288B (2.84 g, 6.05 mmol) inTHF (12 mL) at −78° C. was added diisobutylaluminum hydride (1M inhexane, 10.6 mL, 10.6 mmol). After 0.5 h the reaction was quenched at−78° C. with sat. NH₄Cl (45 mL), 10% sodium potassium tartrate solution(45 mL), diluted with ethyl acetate, and stirred for 1 h at 25° C. Theorganic layer was separated, dried, and the solvent was evaporated togive 2.85 g crude oil used directly for the next step.

ii. The above crude product was stirred in methanol (50 mL) withpyridinium p-toluenesulfonate (0.15 g, 0.59 mmol) at 25° C. for 1 hafter which the mixture was quenched with brine, extracted with ethylacetate, dried, filtered, and the solvent was evaporated to give 2.57 gof an oil which was used directly for the next step.

iii. To a solution of crude product of example 288C(ii) indichloromethane (40 mL) at −78° C. was added trimethylsilyl cyanide (2.1mL, 15.78 mmol) and boron trifluoride-etherate (0.98 mL, 7.76 mmol).After 1 h the reaction was quenched with sat. sodium bicarbonate andwarmed to 25° C. and extracted with dichloromethane. The solvents wereevaporated and the crude residue was purified by column chromatographyon silica gel using 1% methanol/dichloromethane to give the titlecompound (2.48 g, 84% over three steps).

¹H NMR (CDCl₃) δ 5.8-5.68 (m, 1H), 5.56-5.45 (m, 1H), 4.52-4.47 (dd,11H), 4.17-4.08 (m, 2H), 4.05-3.65 (m, 3H), 3.4 (m, 1H), 2.65 (m, 1H),1.97 (d, 1H), 1.66 (dd, 3H), 1.52 (s, 9H), 1.3 (s, 6H), 0.84 (s, 9H),0.12 (dd, 6H).

MS: (M+H)⁺=481, (M+Na)⁺=503.

288D tert-Butyl(2R,3S,5R)-5-cyano-2-((S)-((4R)-2,2-dimethyl-1,3-dioxolan-4-yl)(hydroxy)methyl)-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

To a solution of the product of example 288C (2.48 g, 5.16 mmol) in THF(32 mL) at 0° C. was added tetrabutylammonium fluoride (1M in THF, 10mL, 10 mmol) over 1 h. After 0.5 h the reaction was quenched with sat.NH₄Cl and ethyl acetate. The organic layer was seperated, dried, and thesolvents were evaporated. The crude residue was purified by columnchromatography on silica gel using 15% ethyl acetate/dichloromethane togive the title compound (1.75 g, 92.5%).

¹H NMR (CDCl₃) δ 5.8-5.52 (m, 2H), 4.48 (dd, 1H), 4.15-4.08 (m, 2H),3.93 (dd, 1H), 3.86 (d, 1H), 3.62-3.45 (m, 2H), 2.63 (ddd, 1H), 2.07 (d,1H), 1.68 (dd, 3H), 1.53 (s, 9H), 0.88 (s, 9H), 1.4 (s, 3H), 1.34 (s,3H).

MS: (M+Cl)⁻=401; (M+H)⁺=367, (M+Na)⁺=389.

288E tert-Butyl(2R,3S,5R)-2-((R)-azido((4S)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)-5-cyano-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

To a solution of the product of example 288D (1.75 g, 4.78 mmol) in THF(28 mL) at 0° C. was added sequentially, triphenylphosphine (2.25 g, 8.6mmol), diethyl diazodicarboxylate (1.35 mL, 8.6 mmol), anddiphenylphosphoryl azide (1.85 mL, 8.6 mmol). The reaction mixture wasallowed to warm to 25° C. over 16 h before being quenched with water(100 mL), 10% citric acid (50 mL), and ethyl acetate. The organic layerwas separated, dried, and the solvents were evaporated. The cruderesidue was purified by column chromatography on silica gel using 12%ethyl acetate/dichloromethane to give the title compound (1.25 g, 67%).

¹H NMR (CDCl₃) δ 5.68-5.48 (m, 2H), 4.53 (d, 1H), 4.2-3.97 (m, 3H), 3.83(t, 1H), 3.55-3.30 (m, 2H), 2.74 (ddd, 1H), 1.98 (dt, 1H), 1.68 (dd,3H), 1.53 (s, 9H), 0.88 (s, 9H), 1.46 (s, 3H), 1.37 (s, 3H).

MS: (M+H)⁺=392, (M+Na)⁺=414.

288F tert-Butyl(2R,3S,5R)-2-(1R,2S)-1-(acetylamino)-2,3-dihydroxypropyl)-5-cyano-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

i. To a solution of the product of example 288E (1.25 g, 3.19 mmol) inTHF:water (4:1) (44 mL) was added triphenylphosphine (1 g, 3.84 mmol),and the mixture was heated to 75° C. for 18 h. The solvents wereevaporated and the crude amine was azeotroped with benzene (10 mL).

ii. The crude amine was dissolved in dichloromethane (30 mL) at 25° C.and combined with triethylamine (3.73 mL, 26.8 mmol), acetic anhydride(1.26 mL, 13.4 mmol), and 4-dimethylaminopyridine (0.044 g, 0.34 mmol).After 1 h, water and dichloromethane were added, and the organic layerwas separated and passed through a small pad of silica gel with ethylacetate to give 2.2 g crude acetamide containing triphenylphosphine andused directly for the next step.

iii. The crude N-acetamide (2.2 g) was dissolved in 80% acetic acid (100mL) at 25° C. for 4 days. The solvents were evaporated and the crudeproduct was purified by column chromatography on silica gel using 5%methanol/ethyl acetate to give the title compound (0.92 g, 78% overthree steps).

¹H NMR (CDCl₃) δ 5.94 (d, 1H), 5.8-5.55 (m, 2H), 4.49 (d, 1H), 4.46 (dd,1H), 3.88-3.54 (m, 5H), 3.34 (m, 1H), 3.28 (dd, 1H), 2.65 (m, 1H), 2.16(d, 1H), 2.07 (s, 3H), 1.63 (dd, 3H), 1.56 (s, 9H).

MS: (M−H)⁻=366, (M+Cl)⁻=402; (M+H)⁺=368, (M+Na)⁺=390.

288G tert-Butyl (2R,3S,5R)-2-(1-((R)-1-(acetylamino)-(2R and2S)-2-hydroxypentyl)-5-cyano-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

i. To a solution of the product of example 288F (0.92 g, 2.51 mmol) in30% aqueous ethanol (24 mL) at 0° C. was added sodium metaperiodate (1.6g, 7.48 mmol). The mixture was stirred for 1 h before diluting withethyl acetate. The organic layer was separated, dried, and the solventswere evaporated and azeotroped with toluene to give 19 of crude aldehydewhich was used directly for the next step.

ii. To a solution of propyl magnesium chloride (2M in ether, 3.65 mL,7.3 mmol) in THF (14 mL) at 0° C. was added the product of example288G(i) (1 g) in THF (10 mL) over 0.5 h. The mixture was stirred for 0.5h before being quenched with sat. NH₄Cl, extracted with ethyl acetate,dried, and the solvents were evaporated. The crude residue was purifiedby column chromatography on silica gel using ethyl acetate to give thetitle compounds (0.665 g, 70% as a 3.5:1 mixture of stereoisomers).

Major isomer

¹H NMR (CDCl₃) δ 5.98 (d, 1H), 5.77-5.55 (m, 2H), 4.45 (d, 1H), 4.3 (d,1H), 3.72-3.56 (m, 2H), 3.48 (m, 1H), 3.24 (dd, 1H), 2.7 (m, 1H), 2.14(d, 1H), 2.03 (s, 3H), 1.62 (dd, 3H), 1.55 (s, 9H), 1.5-1.2 (m, 4H),0.88 (t, 3H),

MS: (MH)⁻=378, (M+Cl)⁻=414; (M+H)⁺=380, (M+Na)⁺=402.

Minor isomer:

¹H NMR (CDCl₃) δ 6.7 (d, 1H), 5.68-5.53 (m, 2H), 4.42 (dd, 1H), 4.02 (m,1H), 3.76 (dd, 1H), 3.53 (m, 1H), 3.32 (m, 2H), 2.64 (m, 1H), 2.07 (d,1H), 2.01 (s, 3H), 1.66 (d, 3H), 1.55 (s, 9H), 1.5-1.24 (m, 4H), 0.92(t, 3H).

MS: (M−H)⁻=378, (M+Cl)⁻=414; (M+H)⁺=380, (M+Na)⁺=402.

288H tert-Butyl(2R,3S,5R)-2-((1R)-1-acetylamino)-2-oxopentyl)-5-cyano-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

To the product alcohols of example 288G (0.665 g, 1.75 mmol) indichloromethane (18 mL) was added Dess-Martin reagent (1.05 g, 2.47mmol) at 25° C. After 1.5 h the reaction mixture was diluted with ether(100 mL) and filtered through Celite. The organic solution was washedwith 10% sodium thiosulfate (50 mL), and the solvents were evaporated.The crude residue was purified by column chromatography on silica gelusing ethyl ether to give the title compound (0.5 g, 76%).

¹H NMR (CDCl₃) δ 7.56 (d, 1H), 5.63 (m, 1H), 5.43 (m, 1H), 5.02 (d, 1H),4.45 (dd, 1H), 3.68 (d, 1H), 3.38 (m, 1H), 2.62-2.4 (m, 3H), 2.07 (s,3H), 1.96 (m, 1H), 1.6 (dd, 3H), 1.52 (s, 9H), 1.6-1.48 (m, 2H), 0.88(t, 3H);

MS: (M−H)⁻=376; (M+H)⁺=378, (M+Na)⁺=400.

288I tert-Butyl(2R,3S,5R)-2-((1R,2S)-1(acetylamino)-2-hydroxy-2-methylpentyl)-5-cyano-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

A solution of the product of example 288H (20 mg, 0.053 mmol) in THF(0.5 mL) was added to methyl magnesium bromide (3M in THF, 0.105 mL,0.318 mmol) in THF (1.0 ml) at 0° C. After 0.5 h at 0° C. the mixturewas quenched with sat. NH₄Cl and extracted with ethyl acetate. Theorganic layer was separated, dried, and the solvent was evaporated. Thecrude residue was purified by column chromatography on silica gel usingethyl acetate to give the title compound (10.4 mg, 50%).

¹H NMR (CDCl₃) δ 5.91 (d, J=9.5 Hz, 1H), 5.71 (m, 1H), 5.55 (m, 1H),4.38 (d, J=8.8 Hz, 1H), 4.28 (m, 1H), 3.97 (m, 1H), 3.47 (m, 1H), 2.55(m, 1H), 2.07-2.02 (m, 1H), 2.02 (s, 3H), 1.65 (d, J=6.8 Hz, 3H), 1.56(s, 9H), 1.56-1.30 (m, 4H), 1.14 (s, 3H), 0.93 (m, 3H).

MS: (M+H)⁺=394, (M−H)=392.

288J tert-Butyl(2R,3S,5R)-2-(1R,2S)-1-acetylamino-2-methoxy-2-methylpentyl)-5-cyano-3-((1Z)-1-propenyl-1-pyrrolidinecarboxylate

To a solution of the product of example 288I (16 mg, 0.041 mmol) in THF(0.5 mL) at −78° C. were added methyl iodide (0.125 mL, 2.02 mmol) andNaHMDS (1M in THF, 0.06 mL, 0.061 mmol) and the mixture was stored at−25° C. for 16 h. The reaction was quenched with sat. NH₄Cl and ethylacetate was added. The organic layer was separated, dried and thesolvent was evaporated. The crude residue was purified by columnchromatography on silica gel using 50% ethyl acetate/dichloromethane togive the title compound (7.7 mg, 50%). 1H NMR (CDCl₃) rotamers δ 5.89(m, 1H), 5.71 (m, 1H), 5.50 (m, 1H), 4.55 (dd, J=2.0, 9.2 Hz, 1H), 4.44(t, J=9.5 Hz, 1H), 4.36 (dd, J=1.0, 9.5 Hz, 1H), 3.94 (m, 1H), 3.89 (d,J=1.0 Hz, 1H), 3.73 (dd, J=9.2, 9.8 Hz, 11H), 3.21 and 3.20 (2s, 3H),2.49 (m, 1H), 2.00 (s, 3H), 1.95 (d, J=12.9 Hz, 1H), 1.80-1.20 (m, 4H),1.66 (dd, J=1.7, 6.8 Hz, 1H), 1.55 (m, 9H), 1.14 and 1.12 (2s, 3H), 0.95(t, J=6.8 Hz, 3H).

MS: (M+H)⁺=408, (M−H)⁻=406.

288K (−)-(42R,3S5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

The product of example 288J (2 mg, 0.005 mmol) was combined withhydrochloric acid (6N, 1 mL) and stirred at 60° C. for 16 h. The solventwas evaporated to give the title compound (1.6 mg, quant.).

¹H NMR (MeOD-d₃) δ 5.60 (m, 1H), 5.30 (m, 1H), 4.48 (d, J=9.8 Hz, 1H),4.37 (t, J=8.1 Hz, 1H), 3.65 (t, J=9.5 Hz, 1H), 3.27 (s, 3H), 3.27 (m,1H), 2.57 (m, 1H), 1.93 (s, 3H), 1.72 (m, 1H), 1.62 (dd, J=1.7, 6.8 Hz,3H), 1.70-1.23 (m, 4H), 1.28 (s, 3H), 0.88 (t, J=6.8 Hz, 3H).

MS: (M+H)⁺=327, (M+Na)⁺=349.

EXAMPLE 289(−)(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

289A (2E)-2-Methyl-2-penten-1-ol

A solution of methyl 2-methyl-2-pentenoate (6.37 g, 49.6 mmol) in ether(120 mL) was added to a mixture of lithium aluminum hydride (4.72 g,124.2 mmol) in ether (180 mL) at 0° C. and stirred at 25° C. for 1.5 h.After recooling to 0° C. the reaction was quenched (water, 4.7 mL; 15%NaOH, 4.7 mL; water, 14.1 mL). The mixture was filtered, dried,refiltered, and the solvent was evaporated. The crude product wasdistilled (55 torr, 85-87° C.) to give the allylic alcohol (3.96 g,80%).

¹H NMR (CDCl₃) δ 5.44-5.38 (m, 1H), 4.0 (d, J=5.42 Hz, 2H), 2.10-2.00(m, 2H), 1.67 (s, 3H), 1.0-0.95 (t, J=5.09 Hz, 3H).

289B

A solution of the product of example 289A (5.1 g, 51 mmol) indichloromethane (35 mL) was added to a mixture of (−)-dimethylD-tartrate (0.545 g, 3.06 mmol), titanium tetraisopropoxide (0.76 g,2.55 mmol), molecular sieves (4A, 1.8 g), and t-butyl hydroperoxide (5Msolution in decane, 20 mL) in dichloromethane (180 mL) at −20° C., andthe reaction mixture was stirred for 3.5 h. To this mixture was addedtrimethyl phosphite (9 mL, 76.5 mmol), triethylamine (8.5 mL, 61.2mmol), and benzoyl chloride (5.92 mL, 51 mmol), and was stirred for 1.5h before being washed with 10% tartaric acid (200 mL×2), saturatedsodium bicarbonate (150 mL×3), and brine. The organic layer was dried,the solvent was evaporated and the residue was purified by columnchromatography on silica gel using hexanes-85% hexanes/ethyl acetate togive the title compound (7.35 g, 65%).

¹H NMR (CDCl₃) δ 8.18-7.42 (m, 5H), 4.31 (dd, J=11.87, 6.45 Hz, 1H),2.94 (t, J=6.45 Hz, 1H), 1.71-1.53 (m, 2H), 1.40 (s, 3H), 1.06 (t,J=7.46 Hz, 3H).

289C (2S)-2-Methyl-1,2-pentanediol

To a solution of lithium aluminum hydride (3.8 g, 0.1 mol) at 0° C. intetrahydrofuran (THF) (160 mL) was added the product of example 289B(7.35 g, 0.033 mol) in THF (40 mL). After 0.5 h, the mixture is warmedto 25° C., recooled to 0° C. and quenched (water, 5 mL: 15% NaOH, 5 mL:water, 15 mL). The mixture was filtered, and the solvent was evaporated.The residue was purified by column chromatography on silica gel usinghexanes-60% hexanes/ethyl acetate to give the title compound (2.48 g,63%).

¹H NMR (CDCl₃) δ 3.50-3.38 (m, 2H), 1.50-1.31 (m, 4H), 1.17 (s, 3H),0.94 (t, J=7.1 Hz, 3H).

289D (2S)-1-(Benzyloxy)-2-methyl-2-pentanol

To a suspension of sodium hydride (95% powder, 5.08 g, 0.212 mol) in THF(210 mL) at 0° C. was added the product of example 289C (10.02 g, 0.085mol) in THF (85 mL). After 1 h, benzyl bromide (12.1 mL, 0.102 mol) wasadded, and the reaction mixture was warmed to 25° C. for 16 h. Themixture was quenched with sat. NH₄Cl (30 mL), and the solvent wasevaporated. The residue was partitioned between water and ether, theether was separated and dried. The crude product was purified by columnchromatography on silica gel using 100-85% hexanes-hexanes/ethyl acetateto give the title compound (17.26 g, 98%).

¹H NMR (CDCl₃) δ 7.39-7.27 (m, 5H), (s, 4.56, 2H), 3.31 (dd, J=8.82,16.96 Hz, 2H), 1.52-1.23 (m, 4H), 1.17 (s, 3H), 0.92 (t, J=7.12, 3H).

289E ((((2S)-2-Methoxy-2-methylpentyl)oxy)methyl)benzene

To a solution of the product of example 289D (17.26 g, 0.0829 mol) inTHF (280 mL) at 0° C. was added sodium bis(trimethylsilyl)amide (NaHMDS)(1M in THF, 166 mL, 0.166 mol). After 1 h methyl iodide (25.8 mL, 0.415mol) was added, and the mixture was warmed to 25° C. for 16 h. Themixture was quenched with sat. NH₄Cl (25 mL) and water (250 mL), theorganic layer was separated and the aqueous layer was extracted withether. The organic layers were combined, washed with brine, and dried.The solvent was evaporated, and the residue was purified by columnchromatography on silica gel using hexanes-90% hexanes/ethyl acetate togive the title compound (18.03 g, 98%).

¹H NMR (CDCl₃) δ 7.35-7.26 (m, 5H), 4.55 (s, 2H), 3.32 (dd, J=9.8, 12.5Hz, 2H), 3.22 (s, 3H), 1.58-1.42 (m, 2H), 1.34-1.22 (m, 2H), 1.14 (s,3H), 0.90 (t, J=7.12 Hz, 3H).

289F (2S)-2-Methoxy-2-methylpentanal

To a solution of the product of example 289E (5 g, 22.5 mmol) indichloromethane (75 mL) was added Pd(OH)₂ (20% on carbon, 1.6 g) and theflask fitted with a hydrogen balloon. The mixture was stirred for 3.5 hafter which the catalyst was filtered and rinsed with dichloromethane(75 mL). This solution was reacted directly with pyridiniumchlorochromate (14.5 g, 67.5 mmol) at 0° C. with molecular sieves (4 A,5 g) and Celite (5 g). The mixture was stirred for 1.5 h at 25° C. Ether(200 mL) was added and this solution was filtered through a short pad ofsilica gel with additional ether. The solvent was evaporated in ashort-path distillation apparatus, and the product was distilled (60torr, 72-75° C.) to give the title compound (1 4 g, 48% for two steps).

¹H NMR (CDCl₃) δ 9.21 (s, 1H), 3.28 (s, 3H), 1.64-1.51 (m, 2H),1.38-1.23 (m, 2H), 1.22 (s, 3H), 0.92 (t, J=7.12 Hz, 3H).

289GN-((E,2S)-2-Methoxy-2-methylpentylidene)-(4R)-methylbenzenesulfinimine

To a solution of p-toluenesulfinamide (138.42 mg, 0.892 mmol) in THF (3mL) was added aldehyde product of example 289F (0.143 mL, 1.07 mmol)followed by titanium tetraethoxide (0.57 mL, 2.72 mmol). The solutionwas stirred at 25° C. overnight and quenched by pouring the solutioninto brine (3 mL). The mixture was filtered through a pad of Celite andrinsed with dichloromethane and water. The organic layer was separatedand the aqueous layer was extracted with dichloromethane (2×20 mL). Thecombined organic layers was dried and the solvent was evaporated. Thecrude residue was purified by column chromatography on silica gel using50-33% hexane/dichloromethane, then 1% and 2% Et₂O/dichloromethane togive the title compound (189.19 mg, 79%).

¹H NMR (CDCl₃) δ 8.13 (s, 1H), 7.56 (d, J=8.48 Hz, 2H), 7.30 (d, J=8.47,1H), 3.20 (s, 3H), 2.40 (s, 3H), 1.59 (m, 2H), 1.33 (s, 3H), 1.24 (m,2H), 0.84 (t, J=7.29 Hz, 3H).

MS: (M+H)⁺=268.

289H

To a solution of the product of example 289G (0.278 g, 1.04 mmol) andN-t-butoxycarbonyl-2-t-butyldimethylsilyloxypyrrole (0.59 g, 1.98 mmol),prepared according to the procedure described in JOC, 1992, 57,3760-3763, in dichloromethane (7 mL) at −78° C. was added trimethylsilyltriflate (0.283 mL, 1.56 mmol). After 6 h, the reaction was quenched at−78° C. with triethylamine (0.232 mL, 3.15 mmol) followed by saturatedsodium bicarbonate (5 mL) and dichloromethane and warmed to 25° C. Theorganic layer was separated, dried, and the solvents were evaporated.The crude residue was triturated with ether and the resultedprecipitation was filtered to give the title compound as a white solid(0.25 g, 53%).

¹H NMR (CDCl₃) δ 7.56 (d, 2H), 7.28 (d, 2H), 7.29 (dd, 1H), 5.59 (dd,1H), 4.81 (m, 1H), 4.27 (dd, 1H), 4.18 (d, 1H), 3.18 (s, 3H), 2.39 (s,3H), 1.92 (m, 1H), 1.38-1.72 (m, 3H), 1.69 (s, 9H), 1.43 (s, 3H), 1.03(t. 3H).

MS: (M+H)⁺=451, (M+Na)⁺=473.

289I tert-Butyl(3S)-2-((1R,2S)-2-methoxy-2-methyl-1-(((4-methylphenyl)sulfinyl)amino)pentyl-5-oxo-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

To a suspension of copper bromide/dimethyl sulfide (62.53 mg, 0.30 mmol)in THF (0.6 mL) at −78° C. was added propenylmagnesium bromide (0.5 M inTHF, 1.22 mL, 0.61 mmol).The solution was stirred at −78° C. for 30 min.To the solution was added trimethylsilyl chloride (0.017 mL, 0.13 mmol)followed by a solution of the product of example 289H (54.96 mg, 0.12mmol) in dichloromethane (0.4 mL) at −78° C. The reaction mixture wasstirred at −78° C. for 1.5 h. The reaction mixture was quenched withsat. NH₄Cl and warmed to 25° C. for 1 h. The mixture was partitionedbetween saturated NH₄Cl (10 mL) and dichloromethane (45 mL). The organiclayer was washed with H₂O (10 mL) and the combined aqueous layers wasextracted with dichloromethane (2×10 mL). The combined organic layerswere dried, filtered, and the solvent was evaporated. The crude residuewas purified by column chromatography on silica gel using 17-33% ethylacetate/hexane to give the title compound (44.31 mg, 74%).

¹H NMR (CDCl₃) δ 7.62 (d, J=8.47 Hz, 2H), 7.32 (d, J=8.48 Hz, 2H), 5.43(m, 2H), 4.58 (d, J=7.80 Hz, 1H), 3.99 (br d, J=2.71 Hz, 1H), 3.93 (dd,J=7.80, 2.71 Hz, 1H), 3.71 (m, 1H), 3.19 (s, 3H), 2.57 (dd, J=17.81,9.67 Hz, 1H), 2.40 (s, 3H), 1.97 (dd, J=17.80, 1.53 Hz, 1H), 1.82 (m,1H), 1.59 (s, 12H), 1.52 (m, 1H), 1.42 (s, 3H), 1.27 (m, 2H), 0.96 (t,J=6.95 Hz, 3H).

MS: (M−H)⁻=491; (M+H)⁺=493, (M+NH₄)⁺=510, (M+Na)⁺=515.

289J (1) tert-Butyl(3S,5R)-5-cyano-2-((1R,2S)-2-methoxy-2-methyl-1-(((4-methylphenyl)sulfinyl)amino)pentyl)-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

The title compound was prepared according to the procedure described inexample 288C substituting the product of example 289I for the product ofexample 288B.

¹H NMR (CDCl₃) δ 7.53 (d, J=8.14 Hz, 2H), 7.32 (d, J=8.14 Hz, 2H), 5.73(m, 1H), 5.48 (m, 1H), 4.58-4.46 (m, 2H), 4.01-3.69 (m, 3H), 3.18 (s,0.6H), 3.16 (s, 2.4H), 2.42 (s, 3H), 2.38 (m, 1H), 1.81-1.66 (m, 3H),1.61-1.59 (m, 12H), 1.26-1.17 (m, 5H), 0.92 (m, 3H).

MS: (M−H)⁻=502; (M+H)⁺=504, (M+Na)⁺=526.

289J (2) Alternative Preparation of tert-Butyl(3S,5R)-5-cyano-2-((1R,2S)-2-methoxy-2-methyl-1-(((4-methylphenyl)sulfinyl)amino)pentyl)-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

The title compound was prepared according to the procedure described inexample 288C substituting the product of example 289I for the product ofexample 288B, with the exception that to a solution of crude alcoholresulting from step (i) (following DiBAl-H reduction) (1.21 g, 2.4 mmol)in dichloromethane (12 mL) at −78° C. was added trimethylsilyl cyanide(0.98 mL, 7.2 mmol) and trimethylsilyl triflate (0.64 mL, 3.6 mmol).After 5 minutes the reaction was quenched with sat. sodium bicarbonateand warmed to 25° C. and extracted with dichloromethane. The solventswere evaporated and the crude residue was purified by columnchromatography on silica gel using 40% ethyl acetate/hexane to give thetitle compound (0.82 g).

289K tert-Butyl(2R,3S,5R)-2-((1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl)-5-cyano-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

i. To a solution of the product of example 289J (8.4 mg, 0.017 mmol) inMeOH (0.17 mL) was added trifluoroacetic acid (0.0055 mL, 0.071 mmol) at25° C. The solution was stirred overnight and the solvents wereevaporated. The residue was azeotroped with chloroform and toluene togive an oil, which was used in the next step without purification.

ii. To the crude amine from 289K(i) in dichloromethane (0.17 ml) wasadded triethylamine (0.0238 mL, 0.17 mmol) followed by acetic anhydride(0.0081 mL, 0.086 mmol) at 25° C. The solution was stirred for 20 minand the solvent was evaporated. The residue was purified by columnchromatography on silica gel using 33-67% ethyl acetate/hexane to givethe title compound (5.16 mg, 76% over two steps).

289L(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

The title compound was prepared according to the procedure of example288K.

EXAMPLE 290(−)2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

290A tert-Butyl(2R)-2-((1R,2S)-2-methoxy-2-methyl-1-((tritylsulfenyl)amino)pentyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate

i. A mixture of aldehyde product of example 289F (250 mg, 1.92 mmole),triphenylmethanesulfenamide (560 mg, 1.92 mmole), MgSO₄ (750 mg, 5.7mmole) and PPTS (10 mg, 0.04 mmole) was stirred at 25° C. for 18 hours,filtered and the solvent was evaporated.

ii. To the crude imine from 290A(i) in ether (6.0 ml) at −78° C. wereadded N-t-butoxycarbonyl-2-t-butyldimethylsilyloxypyrrole (1.13 g, 3.8mmole) and BF₃-Et₂O (0.61 ml, 4.8 mmole) and the reaction was stirred at−78° C. for 2 h and then at 40° C. for 2 h. The reaction was quenchedwith sat. sodium bicarbonate (30 ml) and allowed to warm to 25° C. Thereaction was diluted with chloroform (75 ml) and the organic layer waswashed with water and brine, dried, filtered and the solvents wereevaporated. The residue was purified by column chromatography on silicagel using 20% ethyl acetate/hexane to provide the title compound (higherRf) (821 mg, 73%) and a lower Rf diastereomer (187 mg, 17%).

Major diasteomer:

¹H NMR (CDCl₃) δ 7.32 (dd, J=2.0, 6.1 Hz, 1H), 7.29-7.19 (m, 15H), 6.02(dd, J=1.4, 6.1 Hz, 1H), 4.83 (m, 1H), 3.86 (dd, J=3.1, 11.5 Hz, 1H),3.05 (s, 3H), 2.62 (d, J=11.2 Hz, 1H), 1.62-0.98 (m, 4H), 1.36 (s, 9H),0.92 (t, J=6.6 Hz, 3H), 0.43 (s, 3H).

MS: (M+H)⁺=587, (M+Na)⁺=609.

Minor diastereomer:

¹H NMR (CDCl₃) δ 7.28-7.18 (m, 16H), 6.02 (dd, J=1.7, 6.1 Hz, 1H), 4.90(m, 1H), 3.89 (dd, J=2.0, 11.5 Hz, 1H), 3.06 (s, 3H), 2.42 (d, J=11.5Hz, 1H), 1.54 (s, 9H), 1.28-0.85 (m, 4H), 1.16 (s, 3H), 0.57 (t, J=7.1Hz, 3H).

MS: (M+H)⁺=587, (M+Na)⁺=609.

290B tert-Butyl(2R,3S)-2-((1R,2S)-2-methoxy-2-methyl-1-((tritylsulfenyl)amino)pentyl)-5-oxo-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

The title compound was prepared according the procedure of example

288B substituting the product of example 290A for the product of example288A yielding (747 mg, 93%).

¹H NMR (CDCl₃) δ 7.30-7.19 (m, 15H), 5.44-5.33 (m, 2H), 3.99 (d, J=1.4Hz, 1H), 3.69 (m, 1H), 3.58 (dd, J=2.4, 10.5 Hz, 1H), 3.06 (d, J=10.9Hz, 1H), 3.03 (s, 3H), 2.81 (dd, J=9.5, 18.0 Hz, 1H), 1.95 (dd, J=1.4,18.0 Hz, 1H), 1.58 (d, J=5.1 Hz, 3H), 1.62-1.02 (m, 4H), 1.43 (s, 9H),0.86 (t, J=6.6 Hz, 3H), 0.51 (s, 3H).

MS: (M+H)⁺=629, (M+Na)⁺=651.

290C tert-Butyl(2R,3S,5R)-5-cyano-2-((1R,2S)-2-methoxy-2-methyl-1-((tritylsulfenyl)amino)pentyl)-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

The title compound was prepared according the procedure of example 288Csubstituting the product of example 290B for the product of example 288Byielding (459 mg, 71%).

¹H NMR (CDCl₃) δ 7.31-7.20 (m, 15H), 5.74-5.67 (m, 1H), 5.49-5.38 (m,1H), 4.60 (d, J=9.2 Hz, 1H), 3.82 (dd, J=7.8, 10.5 Hz, 1H), 3.79 (d,J=1.7 Hz, 1H), 3.68 (dd, J=2.0, 10.5 Hz, 1H), 3.05 (d, J=10.5 Hz, 1H),3.01 (s, 3H), 2.59-2.48 (m, 1H), 1.84 (d, J=13.2 Hz, 1H), 1.60 (dd,J=1.7, 6.8 Hz, 3H), 1.62-0.90 (m, 4H), 1.34 (s, 9H), 0.86 (t, J=6.6 Hz,3H), 0.45 (s, 3H).

MS: (M+H)⁺=640, (M+Na)⁺=662, (M−H)⁻=638.

290D tert-Butyl(2R,3S,5R)-2-((1R,2S)-1-(acetylamino)-2-methoxy-2-methylpentyl)-5-cyano-3-((1Z)-1-propenyl)-1-pyrrolidinecarboxylate

The product of example 290C (23.0 mg, 0.036 mmole) was suspended inmethanol (1.0 ml) and PPTS (36.0 mg, 0.143 mmol) was added. The mixturewas heated to reflux for 15 h and then the solvent was evaporated. Tothe crude residue dissolved in dichloromethane (0.5 ml) were addedacetic anhydride (0.01 ml, 0.108 mmol) and triethylamine (0.03 ml, 0.216mmol), and the mixture was stirred for 1 h. The reaction was quenchedwith methanol (0.05 ml) and evaporated. The residue was purified bycolumn chromatography on silica gel using a gradient of dichloromethaneup to 50% ethyl acetate/dichloromethane to give the title compound (11.3mg, 77%).

290E(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

The title compound was prepared according to the procedure of example288K.

EXAMPLE 291 tert-Butyl(2R)-2-((1R,2S)-2-methoxy-2-methyl-1-(acetylamino)pentyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate

291A

Ammonia gas was bubbled through a suspension of phenyl disulfide (34 mg,0.15 mmoles) and silver nitrate (26 mg, 0.15 mmol) in methanol (2.5 mL)at 0° C. After 15 min a solution of aldehyde product of example 289F (40mg, 0.3 mmol) in methanol (0.5 mL) was added and the mixture was stirredat 25° C. for 68 h. The reaction mixture was filtered, evaporated,dissolved in ether, refiltered. The organic layer was washed with water,dried, and the solvents were evaporated to give crude imine (42 mg,57%).

291B tert-Butyl(2R)-2-((1R,2S)-2-methoxy-2-methyl-1-(phenylsulfenylamino)pentyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate

A solution of imine product of example 291A (42 mg, 0.18 mmol) andN-t-butoxycarbonyl-2-t-butyldimethylsilyloxypyrrole (53 mg, 0.18 mmol)in dichloromethane (1.5 mL) was cooled to −78° C. and borontrifluoride-etherate (0.034 mL, 0.27 mmol) was added. After 2 h at −78°C. the reaction was quenched with sat. sodium bicarbonate (2 mL),extracted with dichloromethane, dried, and the solvent was evaporated togive the title compound.

291C tert-Butyl(2R)-2-((1R,2S)-2-methoxy-2-methyl-1-(acetylamino)pentyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate

The product of example 291B was treated with 80% acetic acid (2 mL) at25° C. for 1 h and the solvent was evaporated. The crude residue waspurified using 5% methanol in dichloromethane with 0.2% ammoniumhydroxide to give the amine (28 mg, 50%).

The amine product (28 mg, 0.09 mmol) in dichloromethane (1 mL) wastreated with acetic anhydride (0.017 mL, 0.18 mmol), triethylamine(0.028 mL, 0.2 mmol) and 4-dimethylaminopyridine (2 mg, 0.02 mmol) for 1h. The solution was purified by column chromatography on silica geldirectly by eluting with 5% methanol in dichloromethane to give thetitle compound (26 mg, 82%) as a 1.9-1 mixture of two inseparablediastereomers.

Major isomer:

¹H NMR (CDCl₃) δ 7.26-7.30 (dd, 1H), 6.05-6.12 (dd, 1H), 5.33 (d, 1H),4.96-5.01 (dd, 1H), 4.88-4.92 (m, 1H), 3.25 (s, 3H), 1.88 (s, 3H), 1.61(s, 9H), 1.4 (s, 3H), 0.9 (t, 3H).

Minor isomer:

¹H NMR (CDCl₃) δ 7.31-7.35 (dd, 1H), 6.05-6.1 (dd, 1H), 5.37 (d, 1H),4.87-4.92 (dd, 1H), 4.83-4.88 (m, 1H), 3.23 (s, 3H), 1.92 (s, 3H), 1.59(s, 9H), 1.18 (s, 3H), 1.02 (t, 3H).

EXAMPLE 292 tert-Butyl(2R)-2-((1R,2S)-2-methoxy-2-methyl-1-((4-methoxyanilino)pentyl)-5-oxo-2,5-dihydro-1H-pyrrole-1-carboxylate

To a suspension of Yb(OTf)₃ (12 mg, 019 mmole) and MgSO₄ (70 mg, 0.58mmole) in dichloromethane (0.50 ml) were added the aldehyde product ofexample 289F (22 mg, 0.19 mmole) in dichloromethane (0.50 ml) andp-anisidine (24 mg, 0.19 mmole) in dichloromethane (0.50 ml) and themixture was stirred for 0.5 h at rt.N-t-butoxycarbonyl-2-t-butyldimethylsilyloxypyrrole (59 mg, 0.19 mmol)in dichloromethane (0.35 ml) was added and the reaction was stirred for1 h and then quenched with water. The reaction was diluted with ethylacetate and the organic layer was washed with water and brine, dried,filtered and the solvents were evaporated. The residue was purified bycolumn chromatography on silica gel using mixtures of ethylacetate/hexane to provide the title compounds two diastereomers (Yield:higher R_(f) (25 mg, 31%), lower R_(f) (28 mg, 35%)).

Higher R_(f) diasteomer:

¹H NMR (CDCl₃) δ 7.42 (dd, J=2.0, 6.1 Hz, 1H), 6.65 (m, 2H), 6.41 (m,2H), 6.06 (dd, J=1.7, 6.1 Hz, 1H), 4.91 (m, 1H), 4-28 (dd, J=3.4, 10.5Hz, 1H), 3.70 (s, 3H), 3.42 (d, J=10.8 Hz, 1H), 3.26 (s, 3H), 1.90-1.29(m, 4H), 1.52 (s, 9H), 1.18 (s, 3H), 1.02 (t, J=7.1 Hz, 3H).

MS: (M+H)⁺=419, (M+Na)⁺=441.

Lower R_(f) diastereomer:

¹H NMR (CDCl₃) δ 7.39 (dd, J=2.4, 6.1 Hz, 1H), 6.65 (m, 2H), 6.40 (m,2H), 6.05 (dd, J=1.7, 6.1 Hz, 1H), 4.93 (m, 1H), 4.29 (dd, J=2.4, 10.5Hz, 1H), 3.70 (s, 3H), 3.45 (d, J=10.5 Hz, 1H), 3.26 (s, 3H), 1.58 (s,9H), 1.55-1.10 (m, 4H), 1.39 (s, 3H), 0.69 (t, J=7.5 Hz, 3H).

MS: (M+H)⁺=419, (M+Na)⁺=441.

EXAMPLE 293(−)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-ethoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

293A (R)4-(Methoxy-methyl-carbamoyl)-2,2-dimethyl-oxazolidine-3-carboxylic acidtert-butyl ester

The title compound was synthesized according to the procedure of A.D.Campbell, T. M. Raynham, R. J. K. Taylor, Synthesis 1998,1707 fromD-serine, yield 65% (3 steps). [α]_(D)=+36.2 (c=1.8, CHCl₃) [ref.[α]_(D)=+35.8°].

¹H NMR (400 MHz, CDCl₃): δ 4.78 (dd, 0.5H, 1/2 NCH, J=3.5 and 7.4 Hz);4.68 (dd, 0.5H, 1/2 NCH, J=3.5 and 7.4 Hz); 4.15 (m, 1H,); 3.95 (m, 1H,OCH); 3.72 (s, 1.5H, 1/2 OMe); 3.68 (s, 1.5H, 1/2 OMe); 3.18 (s, 3H,Nme); 1.72 (s, 1.5H, 1/2 Me); 1.68 (s, 1.5H, 1/2 Me); 1.58 (s, 1.5H, 1/2Me); 1.54 (s, 1.5H, 1/2 Me); 1.48 (s, 4.5H, 1/2 CMe3); 1.40 (s, 4.5H,1/2 CMe3).

293B (R) 4-But-3-enoyl-2,2-dimethyl-oxazolidine-3-carboxylic acidtert-butyl ester

A solution of the product of example 293A (2.0 g, 6.96 mmol) in dry THF(20 mL) was added a 1.0 M solution of allyl magnesium chloride (14 mL,14 mmol) at −78° C. under N₂. The resulting yellow solution was stirredat −65° C. TLC indicated the absence of S.M. after 1 h. The mixture wasquenched with saturated. NH₄Cl at −65° C. and warmed up to r.t. Afterextraction with EtOAc, the crude product was purified by flashchromatography (EtOAc/hexane 2:8) to give the title compound as acolorless oil (1.74 g, yield 93%).

[α]_(D)=+67.80 (c=2.5, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ 5.90 (m, 1H, ═CH); 5.19 (m, 2H, ═CH); 4.49(m, 0.5H, 1/2 NCH); 4.36 (m, 0.5H, 1/2 NCH); 4.12 (m, 1H, OCH); 3.90 (m,1H, OCH); 3.25 (m, 2H, COCH₂); 1.71 (s, 1.5H, 1/2 Me); 1.65 (s, 1.5H,1/2 Me); 1.52 (s, 1.5H, 1/2 Me); 1.49 (s, 6H, 1/2 Me, 1/2 CMe₃); 1.41(s, 4.5H, 1/2 CMe₃).

MS (FAB): 270.1 (M+1), 214.1, 200.1, 170.1, 156.0, 137.0, 100.1, 83.0,69.0.

HRMS (FAB, NBA): calcd. for C₁₄H₂₄NO₄ (MH) 270.1705, found 270.1713.

293C (4R,1′S)-4-(1-Hydroxy-1-methyl-but-3-enyl)-2,2-dimethyl-oxazolidine3-carboxylic acid tert-butyl ester

To a solution of the product of example 293B (2.69 g, 10 mmol) in 50 mLdry THF was added a 1.4 M solution of MeMgCl (21.43 mL, 30 mmol) at −78°C. The resulting solution was stirred and allowed to warm up to 0° C.over 3 h. After quenching with sat. NH₄Cl, the crude product waspurified by flash chromatography (EtOAc:CH₂Cl₂ 1:9) to give 1.29 g ofstarting material and the title compound (1.37 g , yield 48%) as acolorless oil.

¹H NMR (400 MHz, CDCl₃): δ 5.94 (m, 1H, ═CH); 5.05 (dd, 2H, ═CH, J=6.8and 16.3 Hz); 3.95 (m, 2H, OCH, NCH); 3.85 (d, 1H, OCH, J=7.2 Hz); 2.27(dd, 1H, CH—C═C, J=5.8 and 13.8 Hz); 2.05 (m, (s, 3H, CMe); 1.45 (s, 9H,CMe₃); 1.05 (s, 3H, Me).

¹³C NMR (100 MHz, CDCl₃): δ 155.38, 134.31, 117.46, 94.49, 81.26, 73.99,66.19, 64.63, 41.84, 28.11, 26.05, 24.48, 24.19.

MS (FAB): 286.2(M+1), 230.1, 212.1, 200.1, 186.1, 172.1, 154.1, 144.1,130.0, 110.1, 100.1, 83.0, 69.0.

HRMS (FAB, NBA): calcd. for C₁₅H₂₈NO₄ (MH) 286.2018, found 286.2013.

293D (4R,1′S)-4-(1-Methoxy-1-methyl-but-3-enyl)-2,2-dimethyl oxazolidine3-carboxylic acid tert-butyl ester

To a stirred solution of the product of example 293C (0.5 g, 1.75 mmol)in dry THF (5 mL) was added 218 μl Mel (3.51 mmol) at 0° C., then 60%NaH (77 mg, 1.93 mmol) was added followed by Bu₄NBr (112 mg, 0.35 mmol).The mixture was stirred at r.t. overnight and quenched with H₂O at 0° C.After extraction with EtOAc, the crude oil was purified by flashchromatography (EtOAc:hexane 1:9) to give the title compound as acolorless oil (367 mg, yield 70%).

[α]_(D)=−26.80 (c=4.4, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ 5.83 (m, 1H, ═CH); 5.03 (m, 2H, ═CH₂); 4.14(d, 2H, OCH₂, J=9.2 Hz); 3.82 (dd, 1H, NH, J=6.5 and 9.2 Hz); 3.17 (s,3H, OCH₃); 2.53 (dd, 1H, CH—C═C, J=5.9 and 14.9 Hz); 2.10 (m, 1H,CH—C═C); 1.56 (s, 3H, CMe); 1.45 (s, 12H, CMe, CMe₃); 1.10 (s, 3H, Me).

13C NMR (100 MHz, CDCl₃): δ 154.28, 134.09, 117.23, 80.08, 78.46, 63.77,60.82, 49.35, 39.95, 28.14, 26.59, 24.32, 19.25.

MS (FAB): 300.3 (M+1), 260.2. 244.2, 212.2, 200.2, 186.1, 172.1, 154.1,144.1, 99.1.

293E (1R,2S) (1-Hydroxymethyl-2-methoxy-2-methyl-pent-4-enyl)-carbamicacid tert-butyl ester

To a stirred solution of the product of example 293D (1.09 g, 3.65 mmol)in dry MeOH (30 mL) was added p-toluensulfonic acid (70.4 mg, 0.37 mol)and the resulting mixture was stirred at r.t for 30 min. The reactionwas quenched with sat. NaHCO₃. The solvent was removed under reducedpressure and 20 mL H₂O was added. After extraction with EtOAc, theorganic layer was dried over MgSO₄ and evaporated to give the titlecompound as a white crystalline solid (850 mg, yield 90%).

[α]_(D)=−35.30 (c=0.9, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ 5.75 (m, 1H, ═CH); 5.26 (d, 1H, NH J=8.8 Hz);5.10 (m, 2H, ═CH₂), 3.94 (dd, 1H, OCH J=3.1 and 10.9 Hz); 3.60 (m, 2H,OCH, NCH); 3.21 (s, 3H, OMe); 2.54 (dd, 1H, CH—C═C, J=6.6 and 14.0 Hz);2.29 (dd, 1H, CH—C═C, J=8.0 and 14.0 Hz); 1.43 (s, 9H, CMe₃); 1.24 (s,3H, CMe).

¹³C NMR (CDCl₃): δ 156.24, 132.64, 118.82, 80.68, 79.33, 62.85, 55.78,49.10, 40.09, 29.56, 28.23, 19.27.

MS (FAB): 260.2 (M+1),

242.1, 229.1, 204.1, 172.1, 154.0, 145.1, 136.0, 119.1, 109.1, 95.1,81.1, 69.0.

HRMS (FAB, NBA): calcd. for C₁₃H₂₆NO₄ (MH) 260.1862, found 260.1867.

293F (1R,2S) (1-Hydroxymethyl-2-methoxy-2-methyl-pentyl)-carbamic acidtert-butyl ester

To a solution of the product of example 292E (259 mg, 1.0 mmol) in MeOH(10 mL) was added 15 mmol % of 10% Pd/C. The flask was then flashed withnitrogen and finally with hydrogen. The reaction mixture washydrogenated under atmospheric pressure at r.t. for 14 h, after which itwas filtered through a pad of Celite (3×10 mL EtOH rinse) andconcentrated to give the title compound as a white solid (258 mg, yield99%).

[α]_(D)=−34.10 (c=2.2, CHCl₃).

¹H NMR (CDCl₃): δ 5.20 (d, 1H, NH, J=8.7 Hz); 3.68 (dd, 1H, OCH, J=3.9and 11.1 Hz); 3.55 (m, 2H, NCH, OCH); 3.13 (br, 1H, OH); 3.07 (s, 3H,OMe); 1.55 (m, 1H, CH); 1.32 (s, 9H, CMe₃); 1.25 (m, 3H, CH₂, CH); 1.06(s, 3H, Me); 0.81 (t, 3H, CH₃, J=7.2 Hz).

¹³C NMR (CDCl₃): δ 156.28, 80.13, 78.98, 62.49, 55.77, 48.60, 37.36,28.10, 19.11, 17.01, 14.45.

MS (FAB): 262.2 (M+1), 230.2, 206.1, 174.1, 156.1, 144.1, 123.1, 113.1,101.1, 83.1, 69.1.

HRMS (FAB, NBA): calcd. for C₁₃H28NO₄ (MH) 262.2018, found 262.2024.

293G (1S,2S) (1-Formyl-2-methoxy-2-methyl-pentyl)-carbamic acidten-butyl ester

To a solution of the product of example 293F (190 mg, 0.73 mmol) in dryCH₂Cl₂ (12 mL) was added dry DMSO (2 mL) followed by Et₃N (1.01 mL, 7.3mmol) and Py.SO₃ (928 mg, 5.84 mmol) at 0° C. The resulting mixture wasallowed to warm up to r.t. and stirred for 2 h. The reaction wasquenched with sat. NH₄Cl. After extraction with CH₂Cl₂, the organiclayer was dried over MgSO₄. The solvent was evaporated to give the titlecompound as a crude oil (181 mg, yield 96%) which was used withoutfurther purification.

¹H NMR (400 MHz, CDCl₃): δ 9.63 (s, 1H, CHO); 5.18 (d, 1H, NH, J=7.5Hz); 4.23 (d, 1H, NCH, d=8.0 Hz); 3.09 (s, 3H, OMe); 1.50 (m, 2H, CH₂);1.32 (s, 9H, CMe₃); 1.20 (m, 2H, CH₂); 1.13 (s, 3H, CMe); 0.82 (t, 3H,CH₃, J=7.1 Hz).

¹³C NMR (400 MHz, CDCl₃): δ 201.03, 155.67, 79.69, 79.69, 79.40, 63.58,49.15, 37.12, 28.00, 19.41, 16.37, 14.24.

293H

To a solution of the product of example 292G (272 mg, 1.05 mmol) indichloromethane (20 mL) was added N-p-methoxybenzyl-N-hydroxylamine (153mg, 1.0 mmol) followed by a large excess of MgSO₄. The mixture wasstirred at r.t. for 4 h. After filtration and evaporation the crudeproduct was purified by flash chromatography (EtOAc:hexane 1:1) to givethe nitrone title compound (335 mg, 85%) as a colorless oil.

[α]_(D)=32.30 (c=2.0, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ 7.28 (d, 2H, ArH, J=8.5 Hz); 6.85 (d, 2H,ArH, J=8.5 Hz); 6.64 (d, 1H, NH, J=6.5 Hz); 6.05 (br, 1H, CH═N); 4.83(m, 1H, CHN); 4.77 (s, 2H, CH₂Ar); 3.76 (s, 3H, OMe); 3.09 (s, 3H, OMe);1.37 (s, 9H, Boc); 1.50-1.20 (m, 4H, 2×CH₂); 1.11 (s, 3H, Me); 0.78 (t,3H, CH₃, J=6.2 Hz).

¹³C NMR (400 MHz, CDCl₃): δ 159.94, 155.45, 136.07, 130.63, 124.98,114.10, 80.79, 79.34, 69.51, 55.19, 53.03, 49.40, 37.07, 28.19, 19.43,16.69, 14.56.

293I

To a solution of t-butyl propiolate (505 mg, 4.0 mmol) in dry THF (15mL) at −78° C. was added n-BuLi (1.6 mL, 2.5M in hexanes, 4.0 mmol) andthe resulting solution was stirred for 1 hour. A cold (−78° C.) solutionof nitrone product of example 293H (395 mg, 1.0 mmol) in dry THF (10 mL)was then added with a cannula, followed by BF₃.Et₂O (568 mg, 4.0 mmol).The reaction mixture was stirred at −78° C. for an additional 1 h. Afterbeing quenched with sat. NH₄Cl, (5 mL), the mixture was warmed up tor.t. and extracted with EtOAc (3×25 mL). The organic extracts werecombined, washed with brine, dried over MgSO₄ and filtered. The solventwas removed under reduced pressure and the residue was purified by flashchromatography (EtOAc:hexane 2:8) to give the title compound (417 mg,80%) as a pale yellow oil.

[α]_(D)=−106.5° (c=1.0, CHCl₃).

¹H NMR (400 MHz, CDCl₃): δ 7.29 (d, 2H, ArH, J=8.6 Hz); 6.84 (d, 2H,ArH, J=8.6 Hz); 6.15 (br, 1H, NOH); 5.16 (d, 1H, NH, J=10.8 Hz); 4.25(m, 1H, CHN); 4.12 (s, 2H, CH₂Ar); 3.97 (s, 1H, CHN); 3.79 (s, 3H, OMe);3.11 (s, 3H, OMe); 1.51 (s, 9H, t-Bu); 1.45 (s, 9H, Boc); 1.35-1.20 (m,4H, 2×CH₂); 1.13 (s, 3H, Me); 0.86 (t, 3H, CH₃, J=7.2 Hz).

¹³C NMR (400 MHz, CDCl₃): δ 158.70, 156.99, 152.35, 130.29, 130.03,129.38, 113.44, 83.28, 81.49, 80.04, 77.93, 60.31, 55.10, 48.90, 36.56,28.23, 27.89, 19.58, 16.34, 14.42.

293J(2R,1′R,2′S)-1-p-Methoxybenzyl-2-(1-t-butoxycarbonylamino-2-methoxy-2-methyl)pentyl-5-oxo-2,5-dihydro-1H-pyrrole

To a solution of the product of example 293I (239 mg, 0.5 mmol) in amixture of acetic acid and methanol (1:9, 10 mL) was added zinc dust (20eq., 10 mmol). The reaction mixture was vigorously stirred for 3 h,during which fresh zinc dust (10 eq.) was added. After filtrationthrough a pad of celite, the residue was washed with dichloromethane (20mL) and the filtrate was neutralized by NaHCO₃ at 0° C. The resultingcrude product (after extraction into ethyl acetate, washing with brine,drying over MgSO₄ and evaporation of the solvent) was purified by flashchromatography (EtOAc:hexanes, 4:6) to give the title compound (112 mg,50%) as colorless crystals. The structure and absolute configurationwere confirmed by single crystal X-ray crystallography.

¹H NMR (400 MHz, CDCl₃): δ 7.16 (d, 2H, ArH, J=8.0 Hz); 6.82 (d, 2H,ArH, J=8.0 Hz); 6.16 (d, 1H, ═CH, J=6.0 Hz); 5.27 (m, 1H, ═CH); 4.51 (d,1H, NH, J=10.2 Hz); 4.10 (m, 1H, CHN); 4.09 (s, 2H, CH₂Ar); 3.78-3.75(m, 1H, CHN); 3.76 (s, 3H, OMe); 3.13 (s, 3H, OMe); 1.50-1.40 (m, 2H,CH₂); 1.40 (s, 9H, Boc); 1.13 (s, 3H, Me); 1.09-0.84 (m, 2H, CH₂); 0.62(t, 3H, CH₃).

¹³C NMR (400 MHz, CDCl₃): 171.28, 158.83, 155.94, 145.36, 129.41,129.33, 128.01, 113.89, 113.58, 79.57, 78.26, 60.92, 55.11, 54.09,48.70, 42.44, 37.20, 36.69, 28.16, 27.99, 19.71, 17.13, 14.38.

293K(2R,3S,1′R,2′S)-1-p-Methoxybenzyl-2-(1-t-butoxycarbonylamino-2-methoxy-2-methyl)pentyl-5-oxo-pyrrolidine

The product of example 293J is reacted with the appropriatebis(Z-propen-1-yl)cuprate according to the procedure of Hanessian inSynthetic Letters 1990, p501-505 to provide the title compound.

293L(2R,3S,1′R,2′S)-1-p-Methoxybenzyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-5-oxo-pyrrolidine

The title compound is prepared according to the procedure of 289Ksubstituting the product of example 293K for the product of example289J.

293M(2R,3S,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-5-oxo-pyrrolidine

The product of example 293L is reacted with ceric ammonium nitrateaccording to the procedure of Yamaura in Bull. Chem. Soc. Japan 1985,58, 1413. The resulting product is reacted with di-t-butyldicarbonate,and N,N-dimethylaminopyridine and triethylamine to give the titlecompound.

293N(2R,3S,5R,1′R,2′S)-1-t-Butoxcarbonyl-2-1-acetamido-2-methoxy-2-methyl)pentyl-cyano-5-pyrrolidine

The title compound is prepared according to the procedure described inexample 288C substituting the product of example 293M for the product ofexample 288B.

293O(−)42R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid Hydrochloride Salt

The title compound is prepared according to the procedure of example288K.

EXAMPLE 294(±)-(2R,3R,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-[(aminoimino)methyl]amino-pyrrolidine-5-carboxylicAcid

294A(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(1-hydroxy-2-hydroxy-2-propane)-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The product of example 265A is reacted with osmium tetroxide (0.05 eq.)and 4N-methylmorpholine-N-oxide (3 eq.) in acetone and water at roomtemperature. When complete, the reaction is quenched aqueous sodiumthiosulfate and partitioned between saturated NH₄Cl and ethyl acetate.The organic layer is washed with water, and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue is then purified bychromatography on silica gel providing the title compound.

294B(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-formylpyrrolidine-5-carboxylicAcid t-Butyl Ester.

The product of example 294A with sodium periodate (1.5 eq.) intetrahydrofuran and water at room temerature. When complete, thereaction is quenched with saturated NH₄Cl and diluted with ethylacetate. The organic layer is washed with water, and brine, dried overMgSO₄, filtered and concentrated in vacuo. The residue is purified bychromatography on silica gel providing the title compound.

294C(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-carboxyl-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The product of example 294B is reacted with sodium chlorite (14 eq.) andsodium hydrogen phosphate (10 eq.) in 2-methyl-2-butene, tert-butanol,acetonitrile and water at 0° C. When complete, the reaction is quenchedwith aqueous sodium thiosulfate and diluted with ethyl acetate. Theorganic layer is washed with water, and brine, dried over MgSO₄,filtered and concentrated in vacuo to provide the title compound.

294D (±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The product of example 294C is reacted with diphenylphosphoryl azide(1.2 eq.), triethylamine (1.2 eq.), and benzyl alcohol (1.3 eq.) intoluene at 75° C. When complete, the reaction is quenched with saturatedNH₄Cl and diluted with ethyl acetate. The organic layer is washed withwater, and brine, dried over MgSO₄, filtered and concentrated in vacuo.The residue is then purified by chromatography on silica gel providingthe title compound.

294E(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-amino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The product of example 294F is reacted with 10% palladium on carbonunder an atmosphere of hydrogen in ethanol. When complete, the reactionis diluted with ethyl acetate. The organic layer is washed with water,and brine, dried over MgSO₄, filtered and concentrated in vacuo. Theresidue is then purified by chromatography on silica gel providing thetitle compound.

294F (±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-[(N-tert-butoxycarbonylamino-N′-tert-butoxycarbonylimino)methyl]amino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The product of example E is reacted with1,3-bis(tert-butoxycarbonyl)-2-methyl-2-thiopseudourea (1.5 eq.),triethylamine (5.0 eq.), and mercury(II) chloride (1.5 eq.) in dimethylformamide at room temperature. When complete, the reaction is dilutedwith ethyl acetate and filtered through a pad of celite. The organicsolution is then washed with water, and brine, dried over MgSO₄,filtered and concentrated in vacuo. The residue is then purified bychromatography on silica gel providing the title compound.

294G(±)-(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-[(aminoimino)methyl]amino-pyrrolidine-5-carboxylicAcid.

The product of example 294F is reacted with 80% trifluoroacetic acid indichloromethane at room temperature. When complete, the reaction isconcentrated in vacuo and purified by cation-exchange chromatography onDowex 50W-X8 providing the title compound.

EXAMPLE 295(2R,3R,5R,1′R,2′S)-2-(1Acetamido-2-methoxy-2-methyl)pentyl-3-[(aminoimino)methyl]amino-pyrrolidine-5-carboxylicAcid

295A(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-benzyloxycarbonylamino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared by chiral HPLC chromatography by theprocedure of example 267 substituting the product of example 294D forthe product of example 266 to provide the title compound.

295B(2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-amino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the procedure of example294E substituting the product of example 295A for the product of example294D.

295C (2R,3R,5R,1′R,2′S)-1-t-Butoxycarbonyl2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-[(N-t-butoxycarbonylamino-N′-t-butoxycarbonylimino)methyl]amino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the procedure of example294F substituting the product of example 295B for the product of example294E.

295D (2R,3R,1′R,2′S)-1-t-Butoxycarbonyl2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-[(N-t-butoxycarbonylamino-N′-t-butoxycarbonylimino)methyl]amino-pyrrolidine-5-carboxylicAcid t-Butyl Ester.

The title compound is prepared according to the procedure of example294G substituting the product of example 295C for the product of example294F.

EXAMPLE 296

(2R,3R,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-amino-pyrrolidine-5-carboxylicAcid

The title compound is prepared according to the procedure of example294G substituting the product of example 295B for the product of example294F.

EXAMPLE 297

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicAcid 3-Pentyl Ester

A mixture of 2.92 g (24.5 mmol, 1.79 mL) thionyl chloride and 20 mL of3-pentanol was stirred at room temperature for 45 minutes. To thismixture was added in one portion the product of example 273 (0.40 g,1.23 mmol). The mixture was stirred at room temperature for 18 h andthen the solvent was evaporated in vacuo. The residue was purified bycolumn chromatography on silica gel using 98:2:0.1dichloromethane/methanol/ammonium hydroxide to provide the titlecompound (yield: 0.325 g, 67%) as a colorless oil.

¹H NMR (CDCl₃) δ 5.5-5.25 (m, 3H), 4.77 (m, 1H), 4.16 (dd, J=10.2, 7.2Hz, 1H), 3.84 (t, J=7.5 Hz, 1H), 3.29 (t, J=7.4 Hz, 1H), 3.18 (s, 3H),2.96 (quintet, J=8.3 Hz, 1H), 2.34 (td, J=12.5, 8.2 Hz, 1H), 1.94 (s,3H), 1.62 (dd, J=6.5, 1.3 Hz, 3H), 1.65-1.25 (m, 8H), 1.11 (s, 3H),0.95-0.80 (m, 9H).

MS: (M+H)⁺=397, (M−H)⁻=419, (M−H)⁻=395.

EXAMPLE 298

(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine

The product of example 267 (0.375 g, 1.06 mmol) was reacted withn-propylamine (5 mL) for 5 days room temperature. The reaction wasconcentrated evaporated in vacuo. The residue was purified by columnchromatography on silica gel using 98:2:0.1dichloromethane/methanol/ammonium hydroxide to provide the titlecompound (yield: 0.216 g, 56%) as a white solid.

¹H NMR (CDCl₃) δ 7.57 (m, 1H), 5.82 (d, J=9.5 Hz, 1), 5.45-5.35 (m, 1H),5.24 (m, 1H), 4.09 (dd, J=9.5, 4.8 Hz, 1H), 3.71 (t, J=8.2 Hz, 1H), 3.17(m, 2H), 3.14 (s, 3H), 2.92 (quintet, J=8.4 Hz, 1H), 2.36 (td, J=13.2,7.8 Hz, 1H), 2.01 (s, 3H), 1.61 (dd, J=6.8, 1.7 Hz, 3H), 1.6-1.25 (m,6H), 1.12 (s, 3H), 0.94 (t, J=7.1 Hz, 3H), 0.92 (t, J=7.1 Hz, 3H).

MS: (M+H)⁺=367.

EXAMPLE 299

(±)-(2R,3S,5R,1′R,2′S)-2-(1-Acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine

A mixture of the product of example 267 (0.0085 g, 0.024 mmol) and 3 mLof 2.0M methylamine in water was stirred at room temperature for 24 h,and the solvent was then evaporated in vacuo. The residue was purifiedby column chromatography on silica gel using 98:2:0.1dichloromethane/methanol/ammonium hydroxide to provide the desiredproduct (yield: 0.004 g, 50%) as a colorless oil.

¹H NMR (CDCl₃) δ 7.54 (m, 1H), 5.81 (d, J=9.8 Hz, 1), 5.45-5.35 (m, 1H),5.23 (m, 1H), 4.10 (dd, J=9.5, 4.7 Hz, 1H), 3.73 (t, J=8.1 Hz, 1H), 3.17(dd, J=7.5, 4.7 Hz, 1H), 3.14 (s, 3H), 2.93 (quintet, J=8.5 Hz, 1H),2.79 (d, J=5.1 Hz, 3H), 2.36 (td, J=13.2, 7.8 Hz, 1H), 2.01 (s, 3H),1.60 (dd, J=6.8, 1.7 Hz, 3H), 1.6-1.25 (m, 4H), 1.12 (s, 3H), 0.94 (t,J=7.1 Hz, 3H).

MS: (M+H)⁺=339.

EXAMPLE 300(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxamide

A mixture of 0.0446 g (0.126 mmol))(±)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ethyl ester and 3 mL of conc. ammonium hydroxide was stirred atroom temperature for 24 h, and the solvent was then evaporated in vacuo.The residue was purified by column chromatography on silica gel using95:5:0.1 dichloromethane/methanol/ammonium hydroxide to provide thetitle compound (yield: 0.0185 g, 45%) as a colorless oil.

¹H NMR (MeOH-d₄) δ 5.45-5.25 (m, 2H), 4.09 (d, J=8.8 Hz, 1H), 3.75 (dd,J=8.5, 7.8 Hz, 1H), 3.21 (s, 3H), 3.17 (dd, J=8.7, 7.0 Hz, 1H), 2.96(quintet, J=7.8 Hz, 1H), 2.31 (td, J=12.5, 7.6 Hz, 1H), 1.90 (s, 3H),1.59 (dd, J=6.4, 1.4 Hz, 3H), 1.55-1.25 (m, 5H), 1.23 (s, 3H), 0.87 (t,J=7.1 Hz, 3H).

MS: (M+H)⁺=326, (M+Na)⁺=348, (M−H)⁻=324.

EXAMPLE 301(2R,3S,5R,1′R,2′S)-N-ethyl-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-5-N-ethylcarbamoyl-pyrrolidine

A mixture of 0.0853 g (0.162 mmol)(−)-(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-pyrrolidine-5-carboxylicacid ethyl ester toslyate salt and 5 mL of 70% aqueous ethylamine wasstirred at rt for 24 h, and the solvent was then evaporated in vacuo.The residue was purified by column chromatography on silica gel using97.5:2.5:0.1 dichloromethane/methanol/ammonium hydroxide to provide thedesired product (yield: 0.051 g, 89%) as a white solid.

¹H NMR (CDCl₃) δ 7.51 (m, 1H), 5.83 (d, J=9.5 Hz, 1H), 5.45-5.35 (m,1H), 5.24 (m, 1H), 4.09 (dd, J=9.5, 4.8 Hz, 1H), 3.70 (t, J=7.9 Hz, 1H),3.26 (dq, J=5.8, 7.5 Hz, 2H), 3.16 (m, 1H), 3.14 (s, 3H), 2.92 (quintet,J=8.4 Hz, 1H), 2.35 (td, J=12.9, 7.8 Hz, 1H), 2.01 (s, 3H), 1.61 (dd,J=6.7, 1.5 Hz, 3H), 1.6-1.25 (m, 5H), 1.13 (t, J=7.3 Hz, 3H), 1.12 (s,3H), 0.94 (t, J=7.1 Hz, 3H).

MS: (M+H)⁺=354, (M+Na)⁺=376, (M−H)⁻=352.

EXAMPLE 302(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-5-N-(1-propyl)carbamoyl-pyrrolidinep-Toluenesulfonic Acid Salt

A mixture of(2R,3S,5R,1′R,2′S)-2-(1-acetamido-2-methoxy-2-methyl)pentyl-3-(cis-propen-1-yl)-5-N-(1-propyl)carbamoyl-pyrrolidine(0.213 g, 0.58 mmol) and p-toluenesulfonic acid monohydrate (0.110 g,0.58 mmol) in 5 mL of dichloromethane was stirred at rt for 15 min. Thesolvent was evaporated in vacuo to provide the desired product (yield:0.32 g, 99%) as a white powder.

¹H NMR (CDCl₃) δ 9.35 (bs, 1H), 8.3 (bs, 1H), 8.21 (t, J=5.4 Hz, 1H),7.79 (d, J=8.2 Hz, 2H), 7.16 (d, J=8.1 Hz, 2H), 6.49 (d, J=9.8 Hz, 1H),5.51 (dq, J=10.9, 7.8 Hz, 1H), 5.27 (m, 1H), 4.76 (m, 1H), 4.56 (dd,J=9.8, 7.1 Hz, 1H), 3.81 (m, 1H), 3.42 (m, 1H), 3.25-3.0 (m, 2H), 3.15(s, 3H), 2.72 (dt, J=13.2, 7.5 Hz, 1H), 2.34 (s, 3H), 2.00 (s, 3H), 1.86(m, 1H), 1.64 (s, 3H), 1.57 (dd, J=6.9, 1.5 Hz, 3H), 1.5-1.2 (m, 2H),1.19 (s, 3H), 0.84 (t, J=7.1 Hz, 3H), 0.82 (t, J=6.8 Hz, 3H).

MS: (M+H)⁺=367.

Using the methods described above and the general knowledge of oneskilled in the art, compounds of the invention (having the indicatedrelative stereochemistry or enantiomerically enriched and having theindicated absolute stereochemisty) can be prepared which are representedby taking one core from Table 1 (wherein Ac is acetyl), one Ysubstituent from Table 2, one R substituent from Table 3 and one R³substituent from Table 4a, 4b, 4c, 4d, 4e, 4f, 4 g or 4h.

TABLE 1

TABLE 2

TABLE 3

TABLE 4a

TABLE 4b

TABLE 4c

TABLE 4d

TABLE 4e

TABLE 4f

TABLE 4g

TABLE 4h

The ability of the compounds of the invention to inhibit neuraminidasein vitro can be determined according to the method described below.

Neuraminidase Inhibition Assay:

Influenza virus A/N1/PR/8/34 was grown in the allantoic cavity offertilized eggs and purified by sucrose density gradient centrifugation(Laver, W. G. (1969) in “Fundamental Techniques in Virology” (K. Habeland N. P. Salzman, eds.) pp. 92-86, Academic Press, New York). Influenzavirus A/N2/Tokyo/3/67 was obtained from the tissue culture supernatentsof virus grown on MDCK cells. Neuraminidase from B/Memphis/3/89 viruswas prepared by digestion of the virus with TPCK-trypsin followed bycentrifugation and then purification of the neuraminidase catalyticfragment using sucrose density gradient centrifugation and dialysis asdescribed previously (Air, G. M., Laver, W. G., Luo, M., Stray, S. J.,Legrone, G., and Webster, R. G. (1990) Virology 177, 578587).

The neuraminidase inhibition assays used the neuraminidase enzymaticactivity associated with the A/N1/PR/8/34 or A/N2/Tokyo/3/67 wholevirus, or the B/Memphis/3/89 catalytic head fragment. The whole virus orcatalytic fragment was diluted appropriately with 20 mMN-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer on the day ofthe experiment. Neuraminidase inhibition assays were conducted in 20 mMN-ethylmorpholine, 10 mM calcium choride, pH 7.5 buffer with 5% DMSO.Reaction mixtures included neuraminidase, inhibitor (test compound) and20-30 μM 4-methylumbelliferyl sialic acid substrate in a total volume of200 μL and were contained in white 96-well U-shaped plates. Typically,five to eight concentrations of inhibitor were used for each Ki valuemeasurement. The reactions were initiated by the addition of enzyme andallowed to proceed for 30-60 minutes at room temperature. Thefluorescence for each well of the plate was measured once each minuteduring the reaction period by a Fluoroskan II plate reader (ICNBiomedical) equipped with excitation and emission filters of 355+/−35 nmand 460+/−25 nm, respectively. The plate reader was under the control ofDeltaSoft II software (Biometallics) and a Macintosh computer. If thecompound exhibited linear reaction velocities during the reactionperiod, then the reaction velocities for the dose-response study werefit to equation 1 using a nonlinear regression program (Kaleidagraph) todetermine the overall Ki value (Segel, I. H. (1975) in Enzyme Kinetics,pp. 105-106, Wiley-Interscience, New York).

(1−Vi/Vo)=[I]/{[I]+Ki(1+[S]/Km)}  eqn 1

In equation 1, Vi and Vo represent inhibited and uninhibited reactionvelocities, respectively, and Km=16-40 μM depending on the neuraminidasestrain tested. For those compounds exhibiting slow-binding inhibition(Morrison, J. F. (1982) Trends Biochem. Sci. 7, 102-105), a secondexperiment was performed in a manner identical to the first except thatneuraminidase and inhibitor were preincubated in the absence ofsubstrate for 2 hours at room temperature prior to initiating thereactions with substrate. Data analysis for the resulting linearvelocities was conducted as described above.

Equation 2 was used to measure Ki values in the sub-nanomolar range(Morrison, J. F. And Stone, S. R. (1985) Comments Mol. Cell Biophys. 2,347-368).

 V=A{sqrt{(Ki′+It−Et)̂2+4Ki′Et}−(Ki′+It−Et)]  eqn. 2

In equation 2, V=velocity; A=αkcat[S]/2 (Km+[S]); a is a factor toconvert fluorescence units to molar concentrations; Ki′=Ki(1+[S]/Km);It=total inhibitor concentration and Et=total active concentration ofneuraminidase.

The compounds of the invention inhibit influenza A neuraminidase andinfluenza B neuraminidase with K_(i) values between about 0.1 nanomolarand about 500 micromolar. Preferred compounds of the invention inventioninhibit influenza A neuraminidase and influenza B neuraminidase withK_(i) values between about 0.1 nanomolar and about 3.5 micromolar.

The ability of the compounds of the invention to inhibit plaqueformation in cell culture can be determined by the method describedbelow.

Cell Culture Plague Formation Inhibition Assay

Cell Cultures: MOCK cells obtained from the American Type CultureCollection were grown in Dulbecco's Modified Eagle Medium (DMEM) highglucose (GibcoBRL) supplemented with 10% fetal calf serum (JRHBiosciences), 40 mM HEPES buffer (GibcoBRL) and antibiotics (GibcoBRL).Cells were routinely cultured in flasks or roller bottles at 37° C. and5% CO₂. At confluence cells were reduced to a density of 500,000 cellsin a ml using trypsin/EDTA (GibcoBRL) treatment of the monolayerfollowed by cell centrifugation, resuspension, and dilution into growthmedia. Cells were planted at a volume to surface area ratio of 1 ml over1 cm² of growth surface.

Plaque Assay Protocol: On MDCK cell confluent 6 well plates growth mediawas removed and the cells were overlaid with 1.5 ml of assay media (DMEMwith 1% fetal calf serum, 40 mM HEPES buffer and antibiotics) containingpremixed virus (influenza A/Tokyo/3/67 [H2N2]) (40-100 plaque formingunits) and 2× concentration test compound. The plates were placed on arocker and incubated for 2 hours at room temperature. During the virusadsorption period agar overlay media was prepared. In a microwave oven2× agarose (final concentration of 0.6% agarose) in overlay media (DMEMwith 40 mM HEPES buffer) was melted and then placed in a 48° C. waterbath for temperature equilibration. After the virus adsorption periodwas completed 1.5 ml agar over media was added and mixed with the 1.5 mlvirus and test compound containing media per well.

Cultures were incubated at 35° C. for the period required for plaquedevelopment, usually several days. Plaques were fixed with 3.7% formalinin PBS for 20 minutes followed by removal of the agar overlay andstaining with 0.1% crystal violet in distilled water for 15 minutes.Plaques were counted and EC 50 concentration determined from multipleconcentrations of the tested compound using regression analysis.

Viral Stocks: Stocks were prepared in MDCK confluent roller bottlesincubated at 37° C. in DMEM supplemented with 1% FCS,40 mM HEPES buffer,and antibiotics. Bottles were inoculated with a multiplicity ofinfection of approximately 0.1 plaque forming unit for each cell. Rollerbottles were harvested after the cytopathic effect of the virus wasobserved to be complete. Stocks were prepared from the supernatantresulting from the low speed centrifugation of the media and celllysate. Stocks were titered and stored at −80° C.

Compounds of the invention provided plaque formation inhibition forinfluenza virus A/N2/Tokoyo in MDCK cells with EC50 values between about100 micromolar and about 1 nanomolar. Preferred compounds of theinvention provided plaque formation inhibition for influenza virusA/N2/Tokyo in MDCK cells with EC50 values between about 1 micromolar andabout 1 nanomolar.

The compounds of the invention can be tested for in vivo antiviralactivity using the method described below.

In Vivo Antiviral Efficacy Method

Female BALB/c mice were placed under anesthesia (sevoflurane) andinoculated intranasally (IN) with 0.1 ml of influenza A VR-95 (PuertoRico PR8-34) at 10⁻² (diluted from frozen stock). This viralconcentration consistently produced disease in mice within 5 days ofinoculation. Animals were treated 4h. pre-infection and 4 h.post-infection, and periodically thereafter, with one of the followingtherapies: no treatment; test compound (100, 25, 6.25, 1.39 mg/kg/dayBID, PO); or vehicle (sterile water BID, PO). A group of ten animals(designated as control) was inoculated with 0.9% saline. Percentsurvival was determined. On day five, lungs were harvested, weighed andassigned scores of 0, 1, 2, 3 or 4 based on percentage consolidation (0;10-20; 25-50; 50-75; 75-100%, respectively). In addition, each lung pairwas image analyzed to determine objective lung consolidationpercentages.

The compounds of the present invention can be used in the form of saltsderived from inorganic or organic acids. These salts include but are notlimited to the following: acetate, trifluoroacetate, adipate, alginate,citrate, aspartate, benzoate, benzenesulfonate, bisulfate, butyrate,camphorate, camphorsulfonate, digluconate, cyclopentanepropionate,dodecylsulfate, ethanesulfonate, glucoheptanoate, glycerophosphate,hemisulfate, heptanoate, hexanoate, fumarate, hydrochloride,hydrobromide, hydroiodide, 2-hydroxy-ethanesulfonate (isethionate),lactate, maleate, methanesulfonate, nicotinate, 2-naphthalenesulfonate,oxalate, pamoate, pectinate, persulfate, 3-phenylpropionate, picrate,pivalate, propionate, succinate, tartrate, thiocyanate,p-toluenesulfonate and undecanoate. Also, basic nitrogen-containinggroups can be quaternized with such agents as lower alkyl halides, suchas methyl, ethyl, propyl, and butyl chloride, bromides, and iodides;dialkyl sulfates like dimethyl, diethyl, dibutyl, and diamyl sulfates,long chain halides such as decyl, lauryl, myristyl and stearylchlorides, bromides and iodides, aralkyl halides like benzyl andphenethyl bromides, and others. Water or oil-soluble or dispersibleproducts are thereby obtained.

Examples of acids which may be employed to form pharmaceuticallyacceptable acid addition salts include such inorganic acids ashydrochloric acid, hydrobromic acid, sulfuric acid and phosphoric acidand such organic acids as oxalic acid, maleic acid, succinic acid andcitric acid. Other salts include salts with alkali metals or alkalineearth metals, such as sodium, potassium, lithium, calcium or magnesiumor with ammonium or N(R**)₄ ⁺ salts (where R** is loweralkyl).

In addition, salts of the compounds of this invention with one of thenaturally occurring amino acids are also contemplated.

Preferred salts of the compounds of the invention include hydrochloride,methanesulfonate, p-toluenesulfonate, sulfonate, phosphonate andisethionate.

The compounds of the formula I, IIA, IIB, IIIA or IIIB of this inventioncan have a substituent which is an acid group (for example, —CO₂H,—SO₃H, —SO₂H, —PO₃H₂, —PO₂H). Compounds of the formula I, IIA, IIB, IIIAor IIIB of this invention having a substituent which is an ester of suchan acidic group are also encompassed by this invention. Such esters mayserve as prodrugs. The prodrugs of this invention are metabolized invivo to provide the above-mentioned acidic substituent of the parentalcompound of formula I, IIA, IIB, IIIA or IIIB. Prodrugs may also serveto increase the solubility of these substances and/or absorption fromthe gastrointestinal tract. These prodrugs may also serve to increasesolubility for intravenous administration of the compounds. Prodrugs mayalso serve to increase the hydrophobicity of the compounds. Prodrugs mayalso serve to increase the oral bioavailability of the compounds byincreasing absorption and/or decreasing first-pass metabolism. Prodrugsmay also serve to increase tissue penetration of the compounds, therebyleading to increased activity in infected tissues and/or reduced rate ofclearance.

Such esters contemplated by this invention include:

alkyl esters, especially loweralkyl esters, including, but not limitedto, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl,n-pentyl esters and the like;

alkoxyalkyl esters, especially, loweralkoxyloweralkyl esters, including,but not limited to, methoxymethyl, 1-ethoxyethyl, 2-methoxyethyl,isopropoxymethyl, t-butoxymethyl esters and the like;

alkoxyalkoxyalkyl esters, especially, alkoxyalkoxy-substitutedloweralkyl esters, including, but not limited to, 2-methoxyethoxymethylesters and the like;

aryloxyalkyl esters, especially, aryloxy-substituted loweralkyl esters,including, but not limited to, phenoxymethyl esters and the like,wherein the aryl group is unsubstituted or substituted as previouslydefined herein;

haloalkoxyalkyl esters, especially, haloalkoxy-substituted loweralkylesters, including, but not limited to, 2,2,2-trichloroethoxymethylesters and the like;

alkoxycarbonylalkyl esters, especially, loweralkoxycarbonyl-substitutedloweralkyl esters, including, but not limited to, methoxycarbonylmethylesters and the like;

cyanoalkyl esters, especially, cyano-substituted loweralkyl esters,including, but not limited to, cyanomethyl, 2-cyanoethyl esters and thelike;

thioalkoxymethyl esters, especially, lowerthioalkoxy-substituted methylesters, including, but not limited to, methylthiomethyl, ethylthiomethylesters and the like;

alkylsulfonylalkyl esters, especially, loweralkylsulfonyl-substitutedloweralkyl esters, including, but not limited to, 2-methanesulfonylethylesters and the like;

arylsulfonylalkyl esters, especially, arylsulfonyl-substitutedloweralkyl esters, including, but not limited to, 2-benzenesulfonylethyland 2-toluenesulfonylethyl esters and the like;

acyloxyalkyl esters, especially, loweralkylacyloxy-substitutedloweralkyl esters, including, but not limited to, formyloxymethyl,acetoxymethyl, pivaloyloxymethyl, acetoxyethyl, pivaloyloxyethyl estersand the like;

cycloalkylcarbonyloxyalkyl esters including, but not limited to,cyclopentanecarbonyloxymethyl, cyclohexanecarbonyloxymethyl,cyclopentanecarbonyloxyethyl, cyclohexanecarbonyloxyethyl esters and thelike;

arylcarbonyloxyalkyl esters including, but not limited to,benzoyloxymethyl esters and the like;

(alkoxycarbonyloxy)alkyl esters, especially,(loweralkoxycarbonyloxy)-substituted loweralkyl esters, including, butnot limited to, methoxycarbonyloxymethyl, ethoxycarbonyloxymethyl,1-(methoxycarbonyloxy)ethyl, 2-(ethoxycarbonyloxy)ethyl esters and thelike;

(cycloalkyloxycarbonyloxy)alkyl esters, especially,(cycloalkyloxycarbonyloxy)-substituted loweralkyl esters, including, butnot limited to, cyclohexyloxycarbonyloxymethyl,cyclopentyloxycarbonyloxyethyl, cyclohexyloxycarbonyloxypropyl estersand the like;

oxodioxolenylmethyl esters including, but not limited to,(5-phenyl-2-oxo-1,3-dioxolen-4-yl)methyl,[5-(4-methylphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-methoxyphenyl)-2-oxo-1,3-dioxolen-4-yl]methyl, [5(4-fluorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,[5-(4-chlorophenyl)-2-oxo-1,3-dioxolen-4-yl]methyl,(2-oxo-1,3-dioxolen-4-yl)methyl,(5-methyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-ethyl-2-oxo-1,3-dioxolenyl)methyl,(5-propyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-isopropyl-2-oxo-1,3-dioxolen-4-yl)methyl,(5-butyl-2-oxo-1,3-dioxolen-4-yl)methyl esters and the like;

phthalidyl esters wherein the phenyl ring of the phthalidyl group isunsubstituted or substituted as defined previously herein, including,but not limited to, phthalidyl, dimethylphthalidyl, dimethoxyphthalidylesters and the like;

aryl esters including, but not limited to, phenyl, naphthyl, indanylesters and the like;

arylalkyl esters, especially, aryl-substituted loweralkyl esters,including, but not limited to, benzyl, phenethyl, 3-phenylpropyl,naphthylmethyl esters and the like, wherein the aryl part of thearylalkyl group is unsubstituted or substituted as previously definedherein;

dialkylaminoalkyl esters, especially dialkylamino-substituted loweralkylesters, including, but not limited to, 2-(N,N-dimethylamino)ethyl,2-(N,N-diethylamino)ethyl ester and the like

(heterocyclic)alkyl esters, especially, heterocyclic-substitutedloweralkyl esters wherein the heterocycle is a nitrogenmaintainingheterocycle, including, but not limited to, (heterocyclic)methyl estersand the like, wherein the heterocyclic part of the (heterocyclic)alkylgroup is unsubstituted or substituted as previously defined herein; and

carboxyalkyl esters, especially, carboxy-substituted loweralkyl esters,including, but not limited to carboxymethyl esters and the like;

and the like.

Preferred prodrug esters of acid-containing compounds of the Formula I,IIA, IIB, IIIA or IIIB are loweralkyl esters, including, but not limitedto, ethyl, n-propyl, isopropyl, n-butyl, sec-butyl, isobutyl, t-butyl,n-pentyl esters, 3-pentyl esters, cycloalkyl esters, cycloalkylalkylesters and benzyl esters wherein the phenyl ring is unsubstituted orsubstituted as previously defined herein.

Methods for the preparation of prodrug esters of compounds of theFormula I, IIA, IIB, IIIA or IIIB are well-known in the art and include:

reacting the acid with the corresponding halide (for example, chlorideor acyl chloride) and a base (for example, triethylamine, DBU,N,N-dimethylaminopyridine and the like) in an inert solvent (forexample, DMF, acetonitrile, N-methyl-pyrrolidone and the like);

reacting an activated derivative of the acid (for example, an acidchloride, sulfonyl chloride, monochlorophosphonate and the like) withthe corresponding alcohol or alkoxide salt; and the like.

Other examples of prodrugs of the present invention include amidesderived from the substituent which is an acid group.

Such amides contemplated by this invention include:

simple amides, such as —C(O)NH₂ and the like;

alkylamino amides, especially, loweralkylamino amides, including, butnot limited to, methylamino, ethylamino, n-propylamino, isopropylaminoamides and the like,

cylcoalkylamino amides, including, but not limited to, cylopropylamino,cylcobutylamino, cyclopentylamino, cyclohexylamino amides and the like;

acylamino amides, including, but not limited to acetylamino,propionylamino, butanoylamino amides and the like;

cylcoalkylcarbonylamino amides, including, but not limited to,cyclopropylcarbonylamino, cyclobutylcarbonylamino amides and the like;

alkoxycarbonylalkylamino amides, including, but not limited to,ethoxycarbonylmethylamino, t-butyloxycarbonylmethylamino and the like;

aminoacylamino amides, including, but not limited to, aminoacetylaminoamides and the like;

dialkylaminoacylamino amides, including, but not limited to,dimethylaminoacetylamino, diethylaminoacetylamino amides and the like;

(heterocyclic)acylamino amides, including, but not limited to,piperidin-1-ylacetylamino amides and the like;

amides derived from single naturally occurring L-amino acids (or fromacid-protected L-amino acids, for example, esters of such amino acidsand the like) or from dipeptides comprising two naturally occurringL-amino acids wherein each of the two amino acids is the same or isdifferent (or from acid-protected dipeptides, for example, esters ofsuch dipeptides and the like);

and the like.

Methods for preparation of prodrug amides of compounds of the inventionare well-known in the art and include reacting the acid with theappropriate amine in the presence of an amide bond or peptidebond-forming coupling reagent or reacting an activated derivative of theacid with the appropriate amine and the like.

Other examples of prodrugs of the present invention include esters ofhydroxyl-substituted compounds of formula I, IIA, IIB, IIIA or IIIBwhich have been acylated with a blocked or unblocked amino acid residue,a phosphate function, a hemisuccinate residue, an acyl residue of theformula R¹⁰⁰C(O)— or R¹⁰⁰C(S)— wherein R¹⁰⁰ is hydrogen, lower alkyl,haloalkyl, alkoxy, thioalkoxy, alkoxyalkyl, thioalkoxyalkyl orhaloalkoxy, or an acyl residue of the formulaR^(a)—C(R^(b))(R^(d))—C(O)— or R^(a)—C(R^(b))(R^(d))—C(S)— wherein R^(b)and R^(d) are independently selected from hydrogen or lower alkyl andR^(a) is —N(R^(e))(R^(f)), —OR^(e) or —SR^(e) wherein R^(e) and R_(f)are independently selected from hydrogen, lower alkyl and haloalkyl, oran amino-acyl residue having the formula R¹⁰¹NH(CH₂)₂NHCH₂C(O)— orR¹⁰¹NH(CH₂)₂OCH₂C(O)— wherein R¹⁰¹ is hydrogen, lower alkyl,(aryl)alkyl, (cycloalkyl)alkyl, acyl, benzoyl or an a-amino acyl group.The amino acid esters of particular interest are of glycine and lysine;however, other amino acid residues can also be used, including any ofthe naturally occurring amino acids and also including those wherein theamino acyl group is —C(O)CH₂NR¹⁰²R¹⁰³ wherein R¹⁰² and R¹⁰³ areindependently selected from hydrogen and lower alkyl, or the group—NR¹⁰² R¹⁰³, where R¹⁰² and R¹⁰³, taken together, forms a nitrogencontaining heterocyclic ring.

Other prodrugs include a hydroxyl-substituted compound of formula I,IIA, IIB, IIIA or IIIB wherein the hydroxyl group is functionalized witha substituent of the formula —CH(R¹⁰¹)OC(O)R¹⁰⁵ or —CH(R¹⁰⁴)OC(S)R¹⁰⁵wherein R¹⁰⁵ is lower alkyl, haloalkyl, alkoxy, thioalkoxy or haloalkoxyand R¹⁰⁴ is hydrogen, lower alkyl, haloalkyl, alkoxycarbonyl,aminocarbonyl, alkylaminocarbonyl or dialkylaminocarbonyl. Such prodrugscan be prepared according to the procedure of Schreiber (TetrahedronLett. 1983, 24, 2363) by ozonolysis of the corresponding methallyl etherin methanol followed by treatment with acetic anhydride.

The preparation of esters of hydroxyl-substituted compounds of formulaformula I, IIA, IIB, IIIA or IIIB is carried out by reacting ahydroxyl-substituted compound of formula formula I, IIA, IIB, IIIA orIIIB, with an activated amino acyl, phosphoryl, hemisuccinyl or acylderivative.

Prodrugs of hydroxyl-substituted-compounds of the invention can also beprepared by alkylation of the hydroxyl substituted compound of formulaformula I, IIA, IIB, IIIA or IIIB, with (halo)alkyl esters,transacetalization with bis-(alkanoyl)acetals or condensation of thehydroxyl group with an activated aldehyde followed by acylation of theintermediate hemiacetal.

In preparing prodrugs it often is necessary to protect other reactivefunctional groups, in order to prevent unwanted side reactions. Afterprotection of the reactive groups the desired group can befunctionalized. The resulting functionalized product is thendeprotected, to remove the protecting groups that were added to preventunwanted side reactions. This will provide the desired prodrug. Suitablereaction conditions for preparing protecting groups are well known inthe art. One source for reaction conditions is found in T. H. Greene andP. G. M. Wuts, Protective Groups in Organic Synthesis, 2nd edition. JohnWiley & Sons, New York (1991).

This invention also encompasses compounds of the Formula I, IIA, IIB,IIIA or IIIB which are esters or prodrugs and which are also salts. Forexample, a compound of the invention can be an ester of a carboxylicacid and also an acid addition salt of an amine or nitrogen-containingsubstituent in the same compound.

The compounds of the present invention are useful for inhibitingneuraminidase from diseasecausing microorganisms which comprise aneuraminidase. The compounds of the invention are useful (in humans,other mammals and fowl) for treating or preventing diseases caused bymicroorganisms which comprise a neuraminidase.

The compounds of the present invention are useful for inhibitinginfluenza A virus neuraminidase and influenza B virus neuraminidase, invitro or in vivo (especially in mammals and, in particular, in humans).The compounds of the present invention are also useful for theinhibition of influenza viruses, orthomyxoviruses, and paramyxovirusesin vivo, especially the inhibition of influenza A viruses and influenzaB viruses in humans and other mammals. The compounds of the presentinvention are also useful for the treatment of infections caused byinfluenza viruses, orthomyxoviruses, and paramyxoviruses in vivo,especially the human diseases caused by influenza A and influenza Bviruses.

The compounds of the present invention are also useful for theprophylaxis of infections caused by influenza viruses, orthomyxoviruses,and paramyxoviruses in vivo in humans and other mammals, especially theprophylaxis of influenza A and influenza B viral infections; and, inparticular, the prophylaxis of influenza A and influenza B viralinfections in human subjects who are at high risk of developing otherrespiratory diseases concurrent with or as a consequence of influenzavirus infections, or who suffer from chronic respiratory illness, suchas asthma, emphysema, or cystic fibrosis.

Total daily dose administered to a human or other mammal host in singleor divided doses may be in amounts, for example, from 0.001 to 300 mg/kgbody weight daily and more usually 0.1 to 10 mg/kg body weight daily.Dosage unit compositions may contain such amounts of submultiplesthereof to make up the daily dose.

The amount of active ingredient that may be combined with the carriermaterials to produce a single dosage form will vary depending upon thehost treated and the particular mode of administration.

It will be understood, however, that the specific dose level for anyparticular patient will depend upon a variety of factors including theactivity of the specific compound employed, the age, body weight,general health, sex, diet, time of administration, route ofadministration, rate of excretion, drug combination, and the severity ofthe particular disease undergoing therapy.

Administration of a compound of this invention will begin before or atthe time of infection or after the appearance of established symptomsand/or the confirmation of infection.

The compounds of the present invention may be administered orally,parenterally, sublingually, intranasally, by intrapulmonaryadministration, by inhalation or insufflation as a solution, suspensionor dry powder (for example, in a spray), or rectally, in dosage unitformulations containing conventional nontoxic pharmaceuticallyacceptable carriers, adjuvants, and vehicles as desired. The termparenteral as used herein includes subcutaneous injections, intravenous,intramuscular, intrastemal injection, or infusion techniques.

Injectable preparations, for example, sterile injectable aqueous oroleagenous suspensions may be formulated according to the known artusing suitable dispersing or wetting agents and suspending agents. Thesterile injectable preparation may also be a sterile injectable solutionor suspension in a nontoxic parenterally acceptable diluent or solvent,for example, as a solution in 1,3-propanediol. Among the acceptablevehicles and solvents that may be employed are water, Ringer's solution,and isotonic sodium chloride solution. In addition, sterile, fixed oilsare conventionally employed as a solvent or suspending medium. For thispurpose any bland fixed oil may be employed including synthetic mono- ordiglycerides. In addition, fatty acids such as oleic acid find use inthe preparation of injectables.

Suppositories for rectal administration of the drug can be prepared bymixing the drug with a suitable nonirritating excipient such as cocoabutter and polyethylene glycols which are solid at ordinary temperaturesbut liquid at the rectal temperature and will therefore melt in therectum and release the drug.

Solid dosage forms for oral administration may include capsules,tablets, pills, powders, and granules. In such solid dosage forms, theactive compound may be admixed with at least one inert diluent such assucrose lactose or starch. Such dosage forms may also comprise, as isnormal practice, additional substances other than inert diluents, e.g.,lubricating agents such as magnesium stearate. In the case of capsules,tablets, and pills, the dosage forms may also comprise buffering agents.Tablets and pills can additionally be prepared with enteric coatings.

Liquid dosage forms for oral administration may include pharmaceuticallyacceptable emulsions, solutions, suspensions, syrups, and elixirscontaining inert diluents commonly used in the art, such as water. Suchcompositions may also comprise adjuvants, such as wetting agents,emulsifying and suspending agents, and sweetening, flavoring, andperfuming agents.

The compounds of the present invention can also be administered in theform of liposomes. As is known in the art, liposomes are generallyderived from phospholipids or other lipid substances. Liposomes areformed by mono- or multi-lamellar hydrated liquid crystals that aredispersed in an aqueous medium. Any non-toxic, physiologicallyacceptable and metabolizable lipid capable of forming liposomes can beused. The present compositions in liposome form can contain, in additionto a compound of the present invention, stabilizers, preservatives,excipients, and the like. The preferred lipids are the phospholipids andphosphatidyl cholines (lecithins), both natural and synthetic.

Methods to form liposomes are known in the art. See, for example,Prescott, Ed., Methods in Cell Biology, Volume XIV, Academic Press, NewYork, N.Y. (1976), p. 33 et seq.

While the compounds of the invention can be administered as the soleactive pharmaceutical agent, they can also be used in combination withone or more anti-infective agents and/or other agents used to treatother acute or chronic respiratory ailments. Other agents to beadministered in combination with a compound of the present inventioninclude: an influenza vaccine; other influenza inhibitors such as, forexample, amantadine, rimantadine, ribavirin, and the like; anotherinfluenza neuraminidase inhibitor, such as, for example, zanamivir or GS4104 and the like; agents used to treat respiratory bacterial infectionsand bronchitis, such as, for example, erythromycin, clarithromycin,azithromycin and the like; and agents used to treat asthma, such as, forexample, zileuton, albuterol (salbutamol), salmeterol, formoterol,ipratropium bromide, inhaled steroids and the like, or anti-inflammatoryagents for treating asthma such as, for example, beclomethasonedipropionate, fluticasone propionate, budesonide, triamcinoloneacetonide, flunisolide, cromolyn, zafirlukast, montelukast used incombination with a compound of the present invention.

When administered as a combination, the therapeutic agents can beformulated as separate compositions which are given at the same time ordifferent times, or the therapeutic agents can be given as a singlecomposition.

The foregoing is merely illustrative of the invention and is notintended to limit the invention to the disclosed compounds. Variationsand changes which are obvious to one skilled in the art are intended tobe within the scope and nature of the invention which are defined in theappended claims.

What is claimed is:
 1. A method for inhibiting neuraminidase from adisease-causing microorganism comprising administering to a human orother mammal in need thereof a therapeutically effective amount of acompound of the formula

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein


2. The method of claim 1 wherein the disease-causing microorganism is avirus.
 3. The method of claim 2 wherein the disease-causingmicroorganism is influenza virus.
 4. A method for treating a diseasecaused by a microorganism which has a neuraminidase comprisingadministering to a human or other mammal in need thereof atherapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein


5. The method of claim 4 wherein the disease-causing microorganism is avirus.
 6. The method of claim 5 wherein the disease-causingmicroorganism is influenza virus.
 7. A method for preventing a diseasecaused by a microorganism which has a neuraminidase comprisingadministering to a human or other mammal in need thereof atherapeutically effective amount of a compound of the formula

or a pharmaceutically acceptable salt, ester, or prodrug thereof,wherein


8. The method of claim 7 wherein the disease-causing microorganism is avirus.
 9. The method of claim 8 wherein the disease-causingmicroorganism is influenza virus.